CEREBRAL PHYSIOLOGY AND ANAESTHESIA DRUGS.

1. CEREBRAL PHYSIOLOGY AND
ANAESTHESIA DRUGS
Dr ANZIL A R
DNB RESIDENT (ANAESTHESIOLOGY)

2. ANATOMY OF CEREBRAL CIRCULATION

3. Circle of willis
Normally there is no admixture of blood from anterior and posterior circulations :
same pressure
In pathological circumstances :shunting occurs to increase collateral blood flow to
regions with low blood flow
Anterior cerebral
Anterior communicating
Internal carotid
Posterior communicating
Posterior cerebral

4. Venous drainage
• 3 set of veins drain from brain
1. Superficial cortical veins
2. Deep cortical veins
3. Dural sinuses
• All ultimately drain into
• right and left IJV

5. Most anterior portion of
the cerebrum, controls
motor function
personality, and speech
The most superior portion of the
cerebrum, receives and interprets
nerve impulses from sensory
receptors and interprets language.
The most posterior portion
of the cerebrum, controls visionThe left and right lateral
portion of the cerebrum, controls
hearing and smell

6. REGULATION OF CEREBRAL BLOOD FLOW
• Brain : 1350gm (2% body weight)
• Recieves CBF : 12-15% of C.O. ( 750 ml/min)
• Consumes 3.5 ml Oxygen /100gm/minute = CMRo2
AREA OF BRAIN NORMAL CBF
GLOBAL 45-55ml/100gm/min
CORITCAL(mostly grey matter) 75-85ml/100gm/min
SUBCORTICAL(mostly white
matter)
20ml/100gm/min
GLOBAL
20-25ml/100gm/min Cerebral impairment,slow EEG
15-20ml/100gm.min Flat isoelectric EEG
<10ml/100gm/min Irreversible brain damage

7. • Approximately 60% of the brain’s energy consumption is used
to support electrophysiologic function.
• The remainder of the energy consumed by the brain is involved
in cellular homeostatic activities.
• There are elaborate mechanisms for regulation of CBF which
include chemical , myogenic and neurogenic factors

8. CHEMICAL
MYOGENIC
NEUROGENIC
• CMR,PaCO2,PaO2,
Vasoactive Drugs
• Autoregulation
• Extracranial sympathetic
& parasympathetic
pathway
• Intra axial pathways

9. CHEMICAL FACTORS
CMR(cerebral metabolic rate)
•Increase neuronal activity  increase local brain metabolism 
increase CMR
•Increase in CMR related with proportional changes in CBF is
known as: FLOW METABOLISM COUPLING
•Flow metabolism coupling is a positive feedback mechanism
•Increase activity  increases metabolites (K+, H+, lactate,
adenosine) vasodilatation, pivotal role in increasing CBF
•Increase synaptic activity increases glutamate  generation of
downstream mediators like increase NO vasodilatation

10. • Oxygen modulates relative contribution reduced PaO2 at tissue
level release of adenosine vascular dilatation
• Flow metabolism coupling within brain is therefore a complex
physiological process that is regulated by combination multiple
mechanisms with contribution of metabolic, neural and vascular
factors.
• CMR is influenced by:
1. functional state of CNS:
Increases with pain,anxiety,seizures,acidosis
Decreases with hypothermia,coma,alkalosis
2. Anaesthetic drugs

11. 3. Temperature:
• CMR decrease by 6-7% per degree Celsius of temperature reduction
• Complete suppression of EEG occurs at about 18-20o C
• Reduction of temperature beyond this further reduces CMR
hypothermia decreases rate of energy utilization associated with
maintenance of cellular homeostasis also
• Hyperthermia – between 37-42oC ,CBF and CMR increases
• Above 42o C a dramatic reduction in CMR – toxic effect of
hyperthermia as a result of protein denaturation

12. PaCO2
• CBF varies directly with PaCO2
• CBF changes 1-2mL/100g/min for each 1mmHg change in
PaCO2 around normal values
• This response is attenuated below a value of 25mmHg

13. • Changes in CBF caused by PaCO2 are dependent on pH
alterations in the extracellular fluid of the brain
• CO2 diffuses easily across cerebral vascular endothelium
• CBF changes in response to PaCO2 occurs rapidly but they are
not sustained
• CBF returns to normal as the pH of CSF gradually normalizes
due to extrusion of bicarbonate ions
• Mediators of CO2 induced vasodilation – NO(of neuronal origin)
& in part by prostaglandins

14. Conditions that alter CO2 reactivity
• Severe carotid stenosis
• Head injury
• SAH
• Cardiac failure
• Severe hypotension

15. PaO2
• Below a PaO2 of 60 mmHg, CBF increases rapidly.
• Cerebral vasodilatation in hypoxia may be mediated by peripheral
and neural chemoreceptors & local humoral receptors
• Hypoxia induced opening of ATP dependent K+ channels in
vascular smooth muscles  hyperpolarization vasodilatation
• Stimulation of RVM by hypoxia which is oxygen sensor in brain-
increase in CBF ( no change in CMR)
• Lesions in RVM  suppress response to hypoxia
• Mediators – adenosine, NO

16. • Capacity of cerebral circulation to adjust its resistance to
maintain CBF constant over a wide range of mean arterial
pressure(MAP)
• MAP -> 70-150mmHg (lower limit – 50mmHg)
• Above and below the autoregulatory plateau CBF is pressure
dependent and varies linearly with CPP
• CPP= MAP- ICP
• Normal CPP 80-100mm Hg
• ICP is normally <10 mmHg
• So CPP is primarily dependent on MAP
MYOGENIC REGULATION
(AUTOREGULATION)

17. • Cerebral vascular smooth muscle constricts in response to
an increase in wall tension and relax to a decrease in wall
tension
• At lower limit of autoregulation – vasodilation is maximal
and beyond that CBF falls passively with fall in MAP
• At upper limit – maximal vasoconstriction and beyond that
CBF increases passively with increase in MAP
• The autoregulation curve is shifted to the right in chronic
hypertensive patients and to the left in neonates

18. o Failure of autoregulation may occur in -
 Hypoxemia, hypercapnia,
 High-dose volatile anesthetics
 Ischemic cerebrovascular disease,
 SAH, traumatic brain injury (TBI),
 Tumours
 DM, chronic hypertension

21. Neurogenic regulation of CBF
• Cerebral vasculature is extensively innervated – innervation declines with
vessel size
• Cholinergic, adrenergic, seretonergic, VIPergic systems of extra-axial and
intra-axial origin
• Sympathetic nerves causes vasoconstriction and shifts the autoregulation
curve to right – HTN
• Parasympathetic nerves causes vasodilation and shifts autoregulation curve
to left – hypotension
• Sympathetic denervation produced by stellate ganglion block can increase
CBF

22. Effects of blood viscosity on CBF
Increased CBF Decreased CBF
Anemia polycythemia
decreased hematocrit Increased hematocrit
EFFECT OF AGING
Aging progressively reduce CBF and CMRO2 due to progressive neuronal
loss.

23. Effect of VASOACTIVE DRUGS
SYSTEMIC VASODILATORS:
 Majority of the drugs used to induce hypotension also
cause cerebral vasodilation
 CBF is either increase or maintained at prehypotensive
levels
 ACE inhibitor enalapril has no significant impact on CBF
 Drugs causing cerebral vasodilation – increase in CBV –
increase in ICP

24. CATECHOLAMINE AGONIST & ANTAGONIST
• Effect of these drugs on cerebral vasculature is dependent on:
basal arterial pressure,
magnitude of changes brought by these drugs,
status of autoregulatory mechanism,
status of BBB

25. • α1 agonists – little direct effect on CBF with exception that
norepinephrine may cause vasodilation when BBB is defective
• α2 agonists – dexmedetomidine – dose dependently decreased MCA
flow velocity
Mediated primarily by its ability to suppress CMR
• β agonists – in low doses little effect on CBF
larger doses – increase in CMR & CBF
Defective BBB enhances the effect of β agonists
• β blockers – reduce or have no effect on CBF
catecholamine levels at the time of administration & the
status of BBB may influence the effect

26. • Dopamine – slight vasodilation with minimal
change in CMR
• Dobutamine – 20-30% increase in CMR
• Fenoldopam – 15% reduction in CBF

27. EFFECTS OF ANESTHETICS ON
CBF & CMR

28. INTRAVENOUS AGENTS
• The action of most intravenous anaesthetics leads to parallel reductions in
CMR and CBF
• EXCEPT ketamine which increases both.
• Autoregulation & CO2 responsiveness usually preserved
• CBF/CMR is also dependent on action of IV agents on vasoconstriction,
vasodilatation and alteration of autoregulatory function.

29. BARBITURATES
• Four major action on CNS
• Hypnosis
• Depression of CMR
• Reduction of CBF due to increased cerebral vascular resistance
• Anticonvulsant activity
• Dose dependent reduction in CBF & CMR
• Onset of anaesthesia – 30% reduction in CBF & CMRO2
• Large doses causing complete EEG suppression – 50% reduction
in CBF & CMR
• Further increase in dose have no effect
• CO2 responsiveness preserved

30. •BARBITURATE COMA
•Temporary coma (a deep state of unconciousness) brought on by a controlled
dose of a barbiturate drug, usually pentobarbital or thiopental.
•Barbiturate comas are used to protect the brain during major neurosurgery,
and as a last line of treatment in certain cases of status epilepticus that have
not responded to other treatments
•Barbiturates reduce the metabolic rate of brain tissue, as well as the CBF. With
these reductions, the blood vessels in the brain narrow, decreasing the amount
of volume occupied by the brain, and hence the intracranial pressure.
• The hope is that, with the swelling relieved, the pressure decreases and some
or all brain damage may be averted. Several studies have supported this theory
by showing reduced mortality when treating refractory intracranial
hypertension with a barbiturate coma.

31. PROPOFOL
• Substantial reductions in both CBF and CMR similar to barbiturates
• Surgical levels of propofol reduce regional CBF by 53% to 79% in comparison
with the awake state.
• Propofol primarily reduces in CMR and subsequently decreases CBF,CBV and
ICP
• Both CO2 responsiveness and autoregulation are preserved

32. ETOMIDATE
• Parallel reduction in CBF & CMR
• Agonist at GABA receptors
• At a dose of 0.2mg/kg – 34% & 45% reduction in CBF &
CMR respectively
• Etomidate lower ICP in head injured patients with well
preserved EEG activity but ineffective when antecedent
EEG suppression was present
• CMR suppression regionally variable – predominantly in
forebrain structures
• CO2 reactivity is preserved

33. KETAMINE
• Increases CBF & CMR
• Sub-anaesthetic dose(0.2-0.3mg/kg) – 25% increase in global
CMR
• Greatest increase in frontal & anterior cingulated cortex
• Relative reduction in cerebellum
• (S)-enantiomer – increases CMR
(R)-enantiomer – decreases CMR – temperomedial
cortex & cerebellum
• Increase in ICP correlates with increase in CBF – blunted by
use of other drugs(diazepam, midazolam, isoflurane/N2O,
propofol)
• CO2 responsiveness is preserved

34. BENZODIAZEPINE
• Cause parallel reductions in CBF and CMR
• Maximal reduction in CBF/CMR – in between narcotics & barbiturates
• 0.15mg/kg midazolam – 30-34% decrease in CBF
• CBF and CMRO2 decreased by 25% when 15mg of diazepam was given to
head- injured patients.
• Safe to administer to patients with intracranial hypertension, provided that
respiratory depression and an associated increase in PaCO2 do not occur.
• Flumazenil can reverse CBF, CMR, & ICP lowering effects of midazolam
• Should be used cautiously in patients with impaired intracranial compliance –
increase in ICP

35. FENTANYL:
• Fentanyl – decrease in CBF and CMRO2
• CBF increase – frontal, temporal & cerebellar areas
decrease – discreet areas associated with pain
related processing
• Larger reduction in CBF and CMR during arousal
• CO2 responsiveness & autoregulation unaffected
MORPHINE
• No effect on global CBF and a 41% decrease in the
CMRO2.

36. SUFENTANYL:
• 10mcg/kg – reduction in CBF 22%
• 0.5mcg/kg – no change
• Modest increase in ICP
REMIFENTANYL
• Low doses(0.05 & 0.15mcg/kg) increase CBF
• Higher doses or concomitant administration of other drugs –
no change or modestly reduced
ALFENTANYL:
• No significant changes in CBFV

37. LIDOCAINE:
• Dose related reduction in CMRO2
• 5mg/kg over 30 minutes followed by infusion of
45mcg/kg/min – reduction in CBF(24%) & CMR(20%)
• 1.5mg/kg bolus dose is equally effective as
thiopental(3mg/kg) in controlling acute rise in ICP after skin
incision in craniotomy patients
• Bolus doses – prevention or Rx of acute elevations in ICP
associated with endotracheal suctioning

38. INHALED ANAESTHETICS:
• All volatiles suppress cerebral metabolism in a dose
related manner
• Intrinsic cerebral vasodilator property – direct effect
on vascular smooth muscles
• The net effect is a balance between the two
• At 0.5 MAC – CMR suppression – CBF reduction
occurs
1.0 MAC – CBF unchanged
>1.0 MAC – vasodilator activity predominates –
CBF increases
• Vasodilator property – halothane >> enflurane >
desflurane ~ isoflurane > sevoflurane

39. • 1.0 MAC of isoflurane – 25% in CMRO2
sevoflurane – 38% “ “
desflurane – 22% “ “
• 1.5-2.0 MAC(EEG suppression) of isoflurane caused maximal
reduction in CMRO2 – further increase in dose caused no further
decrease in CMRO2
• Halothane > 4.0MAC(EEG suppression) caused further reduction in
CMRO2 – suggests interference with oxidative phosphorylation –
reversible toxicity
• CO2 responsiveness is maintained
• CBF is preserved up to lower MAP values
• Autoregulation of CBF in response to rising arterial pressures
is impaired

40. • 1.0 MAC of Xenon – decrease in CBF – 15% in cortex & 35% in
cerebellum
• Parallel reduction in CMR – 26%
• Autoregulation & CO2 responsiveness preserved
• The increase in CBF produced by volatile anesthetics and
decrease in cerebral metabolic oxygen requirement at doses
larger than 1 MAC is called uncoupling of flow and
metabolism

41. NITROUS OXIDE:
• Causes increase in CBF, CMR, & ICP – sympatho-
adrenal stimulating effect
• Nitrous oxide alone – dramatic increase in ICP & CBF
• This effect is attenuated by using other drugs –
barbiturates, benzodiazepines, narcotics, propofol
• Increases CMRO2

42. • Vasodilatory action of N2O can be clinically significant in
patients with reduced intracranial compliance
• In circumstances wherein ICP is persistently raised N2O
should be viewed as a potential contributing factor
• N2O should be avoided when a closed intracranial gas
space may exist

43. MUSCLE RELAXANTS:
NDMR:
• Only recognized effect of NDMRs on cerebral vasculature occur via
histamine release
• Histamine – reduction in CPP -> simultaneous increase in
ICP(cerebral vasodilation)and decrease in MAP
• D-tubocurarine – most potent histamine releaser
cisatracurium – least histamine releasing property
• Vecuronium(0.1-0.14mg/kg) had no significant effect on cerebral
physiology

44. • Pancuronium in large bolus dose – abrupt increase in
arterial pressure -> rise in ICP in patients with impaired
intracranial compliance & defective autoregulation
• Muscle relaxation may reduce ICP – coughing and straining
are prevented – lowering of CVP – reduction in cerebral
venous outflow impedence
• In summary, NDMRs are reasonable muscle relaxants in
patients with or at risk of intracranial hypertension
Pancuronium – acute increase in MAP must be prevented

45. SUCCINYL CHOLINE:
• Increase ICP through stimulation of muscle spindles, which
then increases CMR and CBF.
• Poor correlation between visible muscle fasciculation &
increase in ICP
• Deep anaesthesia – prevent succinyl choline induced rise in
ICP

46. The cerebrospinal fluid (CSF)
• Provides mechanical protection for the brain and the spinal
cord.
• When floating in the CSF brain weighs only 50g (!) according
to the Archimedes’ principle.

47. • Cerebrospinal fluid (CSF) is a clear fluid present in the ventricles of the brain, the
central canal of the spinal cord, and the subarachnoid space.
• CSF is produced in the brain by modified ependymal cells in the choroid plexus
(approx. 50-70%), and the remainder is formed around blood vessels and along
ventricular walls.
• Involves active secretion of Na+ in the choroid plexus
• Normal CSF production: 21ml/hr = 500ml/day
• Total CSF volume is 150ml

48. CSF CIRCULATION

49. Lateral ventricle
Intra ventricular foramina of Monro
III Ventricle
Cerebral aqueduct of sylvius
IV ventricle
Foramen of Megendic and foramen of Luschka
Cerebellomedullary cistern (cisterna magna)
Absorbed in arachnoid space circulating around the brain and spinal cord
Absorbed in arachnoid granulations over the cerebral hemispheres
into cerebral venous sinuses
CSF

50. Blood/Brain-Blood/CSF Barriers
 The blood-brain barrier (BBB) is the specialized system of
capillary endothelial cells that protects the brain from harmful
substances in the blood stream, while supplying the brain with
the required nutrients for proper function.
 Formed by the nonfenestrated capillaries and to much lesser
degree, the astrocytic foot processes—keeps out most
macromolecules

51. Blood-CSF
Barrier
The choroid plexus is composed of fenestrated
capillaries and an epithelial (ependymal) covering,
which reverts from "tight" to moderately "open" at
the base -–not as strenuous of barrier as blood/brain

52. Circumventricular organs
• “Circumventricular” = around the ventricles
• Incomplete or missing BBB
• Highly capillarized structures
• Secretion of neurohormones or detection of
hormones, glucose, ions, etc.

53. Intracranial pressure
• Pressure exerted by cranium on brain tissue,CSF and
brain circulating blood volume
• Normal ICP - 7-15 mm hg
• Normally small increase in volume of one compartment
are initially well compensated,however further increases
produces precipitous change in ICP
• Compensatory mechanisms
– Displacement of CSF from cranial to spinal
compartment
– Increase in CSF absorption
– Decrease in CSF production
– Decrease in total cerebral blood volume

54. Causes of Raised ICP
• Physiological
– Fever,seizures,hypothermia,hypoventilation
– Hypoxia,hypercarbia,excess fluids,hypertension
– Intubation and head down tilt
• Pathological
– Increased brain tissue(tumour,abscess,hematoma)
– Increased CSF volume(hydrocephlous,blocked shunt)
– Increased blood volume(hypoxia,hypercarbia,venous
obstruction )

55. Effects of raised ICP
• Cerebral ischemia
• Impaired autoregulation
• Herniation of brain
– The cingulate gyrus under the falx cerebri
– The uncinate gyrus through the tentorium cerebelli
– The cerebrall tonsills through the foramen magnum
– An area beneath a defect in skull