Mechanisms of cerebral injury and cerebral protection

1. Presentor : Dr . Kumar
Moderator :
Dr.Prabhavathy
Mechanism
s of
cerebral
injury
&
Cerebral
protection

2.  “ PHINEAS GAGE “
 first reported case
of personality
change after brain
injury

3. Definition
 “damage to the brain resulting from external
mechanical force, such as rapid acceleration
or deceleration, impact, blast waves, or
penetration by a projectile”

4. Cerebral physiology
 CEREBRAL METABOLISM:
1. brain is normally responsible for consumption of
20% of total body oxygen.
2. Most of cerebral oxygen consumption (60%) is
used in generating adenosine triphosphate (ATP)
to support neuronal electrical activity
3. The cerebral metabolic rate (CMR) is usually
expressed in terms of oxygen consumption
(CMRO2), which averages 3–3.8 mL/100 g/min
(50 mL/min) in adults

5.  high oxygen consumption and the absence of
significant oxygen reserves, interruption of cerebral
perfusion usually results in unconsciousness.
 The hippocampus and cerebellum appear to be
most sensitive to hypoxic injury.

6.  CEREBRAL BLOOD FLOW:
1. CBF varies with metabolic activity.
2. It is most commonly measured with a -emitting
isotope such as xenon (133Xe).
3. total CBF averages 50 mL/100 g/min,
4. flow in gray matter is about 80 mL/100 g/min,
5. white matter is estimated to be 20 mL/100
g/min.
6. Total CBF in adults averages 750 mL/min (15–
20% of cardiac output

7. If CBF is altered
 20–25 mL/100 g/min - cerebral impairment
 15 and 20 mL/100 g/min - flat (isoelectric) EEG
 10 mL/100 g/min - irreversible brain damage.

8. REGULATION OF CBF
 Intrinsic mechanisms
a) Cerebral perfusion pressure
b) Auto regualtion
 Extrinsic mechanisms
a) Respiratory Gas tensions
b) Temperature
c) Viscosity
d) Autonomic influences

9. Cerebral perfusion pressure
 It is the difference between mean arterial pressure
(MAP) and intracranial pressure (ICP) (or central
venous pressure [CVP], whichever is greater).
MAP – ICP (or CVP) = CPP.
 CPP is normally 80–100 mm Hg
 Moderate to severe increases in ICP (> 30 mm Hg)
can significantly compromise CPP and CBF even in
the presence of a normal MAP

10.  CPP values
1. less than 50 mm Hg - slowing on the EEG,
2. 25 and 40 mm Hg - flat EEG.
3. less than 25 mm Hg - irreversible brain damage.

11. Autoregulation
 the brain normally tolerates wide swings in blood
pressure with little change in blood flow.
 changes in MAP will lead to transient changes in
CBF
 Normal MAP - 60 and 160 mm Hg
 Beyond these limits, blood flow becomes pressure
dependent
 Pressures above 150–160 mm Hg can disrupt the
blood–brain barrier and may result in cerebral
edema and hemorrhage

12.  Beyond these limits, blood flow becomes pressure
dependent
 .Pressures above 150–160 mm Hg can disrupt the
blood–brain barrier and may result in cerebral
edema and hemorrhage

13. Myogenic and Metabolic mechanisms
 Myogenic mechanisms involve an intrinsic response
of smooth muscle cells in cerebral arterioles to
changes in MAP
 Metabolic mechanisms indicate that cerebral
metabolic demands determine arteriolar tone.
 when tissue demand exceeds blood flow, the release
of tissue metabolites causes vasodilation and
increases flow

14. Respiratory Gas Tensions
 PaCO2 and PO2
 CBF is directly proportionate
to PaCO2 between tensions of
20 and 80 mm Hg
 Blood flow changes 1–2
mL/100 g/min per mm Hg
change in PaCO2.
 effect is almost immediate
and is due to secondary to
changes in the pH of CSF and
cerebral tissue.

15.  Only marked changes in PaO2 alter CBF.
 hyperoxia may be associated with only minimal
decreases (–10%) in CBF
 severe hypoxemia (PaO2 < 50 mm Hg) profoundly
increases CBF

16. Temperature
 CBF changes 5–7% per 1°C change in temperature.
 Hypothermia decreases both CMR and CBF,
whereas pyrexia has the reverse effect.
 for every 10° increase in temperature, the CMR
doubles.
 the CMR decreases by 50% if the temperature of the
brain falls by 10°C,

17.  At 20°C, the EEG is isoelectric, but further decreases
in temperature continue to reduce CMR throughout
the brain.
 Above 42°C, oxygen activity begins to decrease and
may reflect cell damage

18. Viscosity
 Normally, changes in blood viscosity do not
appreciably alter CBF.
 The most important determinant of blood viscosity
is hematocrit.
 A decrease in hematocrit decreases viscosity and
can improve CBF.
 a reduction in hematocrit also decreases the
oxygen-carrying capacity and thus can potentially
impair oxygen delivery.

19.  Elevated hematocrits with marked polycythemia,
increase blood viscosity and can reduce CBF.
 Some studies suggest that optimal cerebral oxygen
delivery may occur at hematocrits of approximately
30%.

20. Autonomic Influences
 Intracranial vessels are innervated by sympathetic
(vasoconstrictive), parasympathetic (vasodilatory),
and noncholinergic nonadrenergic fibers
 serotonin and vasoactive intestinal peptide appear
to be the neurotransmitters .
 Innervation of large cerebral vessels by
sympathetic fibers originating in the superior
cervical sympathetic ganglia.

21.  Intense sympathetic stimulation induces marked
vasoconstriction in these vessels, which can limit
CBF.
 Autonomic innervation play an important role in
cerebral vasospasm following brain injury and
stroke.

22. Pathophysiology of Brain
Injury
 Two types of brain injuries
 Primary Brain Damage :
Irriversible damage
2 types;
-Focal-Direct impact of skull
into brain causing contusion,
laceration, or hemorrage.
-Diffuse-Difused axonal injury
due to internal shearing,
streaching tearing forces

23.  Secondary Brain Damage
 Factors that causing ischaemia and further brain
damage.
Potentially reversible-role of cerebral protect
-Hypoxia
-Hypotension
-Hypercarbia
-Cerebral edema-cytotoxic/vasogenic
-Herniation

26. INTRACRANIAL PRESSURE
 The cranial vault - fixed total
volume
 brain (80%), blood (12%), and
CSF (8%)
 increase in one component
must be offset by an equivalent
decrease in another to prevent
a rise in ICP

27. compensatory mechanisms
 (1) an initial displacement of CSF from the cranial
to the spinal compartment,
 (2) an increase in CSF absorption,
 (3) a decrease in CSF production, and
 (4) a decrease in total cerebral blood volume
(primarily venous

28. Monro- Kelly Doctrine
 The intracranial Volume is fixed apart from some
minimal ‘give’ due to meninges and foremina
60% fliuds; 40% solid
 All the structures are incompressible for practical
purpose
Increase in the volume one of the compartment must
be buffered by others( spartial compensation)
 Later-Increase in volume within cranium lead to rapid
increase in pressure(elastance)
Raise ICP---reduce CPP
Reduce CPP---Cerebral ischaemia---Infraction ---
Brain death

29. Signs of ICP
 CUSHINGS’S TRIAD
a slow heart rate with high blood
pressure and respiratory
depression is a classic
manifestation of significantly
raised ICP.
 Anisocoria, unequal pupil
size, is another sign of serious
TBI
 Abnormal posturing, a
characteristic positioning of the
limbs caused by severe diffuse
injury or high ICP, is an

30. Assessment of Severity

31. Cerebral Protection
 Methods attempt to reduce the effects of Cerebral
Ischaemia and damage, in order to improve
neurological out comes
 Protective measures before the second insults.
 Possible neuronal recovery after period of
ischaemia Brain must be ‘protected’ from such
insult

32. Strategies :
1.Maintained adequate O2 supply-CPP & PaO2
2.Reduce/prevent raise in ICP
3.Reduce CMRO2
4.Reducing cell damage

33. Indications…
1.Post successful CPR
2.Post carotid Cerebral Protection artery surgery
3.Head injury
4.Compression - Tumour,hematoma
eg : Subdural Hematoma/Intraparenchymal.
5.Inflammatory – Meningitis.
6.Metabolic encephalopathies eg : Reyes Syndrome.
7.CVA / Cerebral haemorrhage

34. Principles Of Management
1. Position
- neutral position
- head elevate to 30°c to 45°c.
2. Observation
- vital sign, GCS and pupillary changes.
3. Maintaining O2 / Ventilation
- hyperventilate ~ keep PCO2 30 – 35mmHg
- maintain PaO2 100mmHg with low PEEP

35. 4. Control Blood Pressure
- maintain MAP ~ 70 – 100mmHg
- maintain adequate cerebral perfusion pressure
(CPP)
CPP = MAP – ICP
5. Diuretics
- osmotic diuretic ( Mannitol 20% )
- loop diuretic ( Frusemide )
6. Fluid Therapy
- control fluid therapy ~ avoid hypovolemia
- use Normal Saline or Hartmann

36. 7. Prevent Isometric Exercise
- eg: give IV Fentanyl before suctioning or any
procedure
8. Steroids
eg. Dexamethasone
- for brain tumour
- reduce cerebral oedema
9. Treatment Of Epilepsy
eg. Diazepam or Phenytoin
- control seizures to reduce cerebral metabolic rate

37. 10. Temperature Control
- maintain normothermia and avoid hyperpyrexia
11. Calcium Antagonist ( Nimodipime )
- for subarachnoid haemorrhage to reduce
cerebral spasm
12. Surgery
- to remove mass or lession
eg. Craniotomy,evacuation of clot,CSF drainage.

38. 13. Nutrition
- early enteral feeding ~ high nutrient and protein
( to prevent infection )
14. Electrolytes
- regular monitoring of
electrolytes,urea,creatinine,blood sugar,
osmolality are important to determine fluid and
electrolyte
therapy.

39. Maintain CPP & O2 supply
Subject to CPP=MAP-ICP and O2 Content
1. Maintain normotension,
2. Keep CVP 5-10 cm H2O
3. Reduce ICP-Head up 15-30 deg. with neutral
position
Consider inotropes
4. No PEEP
5. Hypotension & hypoxia significantly increase
mortality and morbidity
6. Hypotension profoundly increase mortality up to
150%

40. Reduce @ preventing Rise in
ICP
 -Reduce cerebral edema/ICF
1. Mannitol, frusemide
2. Fluid restriction -2/3 maintenance
3. IPPV /hyperventilation;Aim To maintain pCO2
between 30-35mmHg to prevent
hypercapnia(Cereb.Steal Synd)
4. ICP reduces by 30% per 10mmHg reduction in
CO2
5. Prevention hypoxia-cytotoxic cerebral edema
6. Acute change in hyperventilation return to normal
value after 48H, normalise CSF pH and

41. 7. Surgical decompression - craniotomy
8. Normothemia/hypothermia at 35 C Reduce
CMRO2
9. CSF Drainage-via ventriculostomy catheter
10. Encourage venous drainage-head at 15-30 deg
& neutral position
11. Steroids
12. hyperglycaemia- to start insulin

42. Reduce CMRO2
1. Normothermia@Hypothermia
2. Barbiturate/sedation
3. Anticonvulsants phenytoin , Diazepam
4. Muscle relaxants-avoid pancuronium, succinyl
choline
5. Adequate Analgesia

43. Reduce cell damage
1. Avoidance of hyperglycaemia
2. Ca2+ channel blocker-nimodipine
3. Free radical scavanger ie barbiturate,Vit C,E
4. Glutamate and NMDA receptor antagonist

44. Effect of Anaesthetic Drugs
 Barbiturates :
 Barbiturates have four major actions on the CNS:
(1) hypnosis,
(2) depression of CMR,
(3) reduction of CBF due to increased cerebral vascular
resistance, and
(4) anticonvulsant activity

45. o principally to suppression of CMR
o Barbiturate-induced EEG suppression
o effects of CBF redistribution and free radical
scavenging have been suggested to contribute,
and there is evidence that CMR suppression is
not the sole mechanism
o various barbiturates (thiopental, thiamylal,
methohexital, pentobarbital) have similar effects
on CMR and have generally been assumed to
have equal protective efficacy

46.  Benzodiazepines:
o Benzodiazepines cause parallel reductions in
CBF and CMR
o CBF and CMRO2 decreased by 25% when 15 mg
of diazepam was given to head-injured patients
o effects of midazolam on CBF (but not CMR)
o Increase in CSF absorption , Decreases CBV &
ICP

47.  VOLATILE ANESTHETICS:
o Isoflurane - a potent suppressant of CMR in the
cerebral cortex, and EEG evidence suggestive of a
protective effect in humans
o More recent data have shown that long-term
neuroprotection with isoflurane is achievable under
conditions in which the severity of ischemia is limited
and restoration of blood flow after ischemia is
complete
o Sevoflurane reduces ischemic injury
o Desflurane also reduces neuronal injury to the same
extent that isoflurane

48.  Isoflurane, on the other hand, facilitates absorption and is therefore
the only volatile agent with favorable effects on CSF dynamics
 circulatory steal phenomenon :
“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.”
 net effect of volatile anesthetics on ICP is the result of immediate
changes in cerebral blood volume, delayed alterations on CSF
dynamics, and arterial CO2 tension

49.  Propofol :
o EEG suppression can also be achieved with
clinically feasible doses of propofol
o Durable protection with propofol is achievable if the
severity of the ischemic insult is mild
o cerebral infarction was significantly reduced in
propofol-anesthetized
o propofol reduce ischemic cerebral injury

50.  ETOMIDATE
o It too produces CMR suppression to an extent
equivalent to barbiturates.
o administration of etomidate results in greater tissue
hypoxia and acidosis
o aggravation of injury produced by etomidate (an
imidazole) may be related to direct binding of NO as a
consequence of etomidate-induced hemolysis .
o combined with direct inhibition of the NO synthase
enzyme by etomidate.
o no scientific support for the current use of
etomidate for “cerebral protection”

51.  OPIOIDS :
o opioids generally have minimal effects on CBF, CMR, and
ICP, unless PaCO2 rises secondary to respiratory
depression
o hypotension Significant decreases in blood pressure
adversely affect CPP regardless of the opioid selected
o Normeperidine, a metabolite of meperidine, can induce
seizures, cardiac depression

52.  Ketamine:
o dilates the cerebral vasculature and increases CBF (50–
60%)
o Ketamine may also impede absorption of CSF without
affecting formation
o Seizure activity in thalamic and limbic areas is also
described
o Increases in CBF, cerebral blood volume, and CSF volume
can potentially increase ICP markedly in patients with
decreased intracranial compliance

53.  CALCIUM CHANNEL BLOCKERS
o administer nimodipine orally beginning as soon
as possible after subarachnoid hemorrhage.
o it has not yet become standard practice to
administer nimodipine or any other calcium
channel blocker routinely after neurologic stroke
o stroke victims have confirmed the benefits of
nimodipine

54.  XENON:
o inert gas xenon exerts its anesthetic action by
noncompetitive blockade of NMDA receptors
o neuroprotection against excitotoxic injury
o simultaneous administration of subanesthetic doses
of xenon in combination with either hypothermia or
isoflurane significantly reduces neuronal injury and
improves neurologic function
o specific use of xenon for the purpose of
neuroprotection awaits results from outcome studies

55.  LIDOCAINE:
o Intravenous lidocaine decreases CMR, CBF, and ICP but
to a lesser degree than other agents.
o decreases CBF (by increasing cerebral vascular
resistance) without causing other significant
hemodynamic effects.
o The risks of systemic toxicity and seizures, however,
limit the usefulness of repeated dosing

56.  VASOPRESSORS:
o normal autoregulation
- vasopressors increase CBF only when MAP is below
50–60 mm Hg or above 150–160 mm Hg.
o absence of autoregulation:
-vasopressors increase CBF by their effect on CPP. Changes
in CMR generally parallel those in blood flow
o Adrenergic agents have a greater effect on the brain when
the blood–brain barrier is disrupted.
o central B1-receptor stimulation increases CMR and blood
flow.

57.  Neuromuscular Blocking Agents:
o lack direct action on the brain but can have important
secondary effects
o Hypertension and histamine-mediated cerebral vasodilation
increase ICP, while systemic hypotension (from histamine
release or ganglionic blockade) lowers CPP.
o Succinylcholine can increase ICP, result of cerebral
activation associated with enhanced muscle spindle activity
o increases in ICP following administration of an NMBA are the
result of a hypertensive response due to light anesthesia
during laryngoscopy and tracheal intubation

58.  OSMOTIC DIURETICS:
 First line treatment to decrease high ICP
 Induce plasma expansion
i. Reduced hematocrit
ii. Reduced plasma viscosity
iii. Reduced CBV
iv. Mobilization of ECF
 Early high does of mannitol shown to improve long
term outcomes

59.  MAGNESIUM:
o Membrane stabilizer
o Suggested protective mechanism:
 Reduction of presynaptic release of glutamate
 Blockade of NMDA receptors
 Smooth muscle relaxation
 Improved mitochondrial Ca2+ buffering
 Blockage of Ca2+ entry
o Protection depends on:
 Time of treatment initiation
 Type of cerebral ischemia

60.  STEROIDS:
o Suggested protective mechanisms:
1. Increase lipid bilayer
2. Free radical scavenging
3. Reduces cerebral edema
4. Anti-inflammatory effects
5. Prevents FFA accumulation
6. Inhibits lipid peroxidation
o Not shown to decrease morbidity of mortality in
acute cerebral ischemia
o Not recommended for head trauma
o Methylprednisolone: mild benefits in acute spinal
cord injury

61. EFFECTS OF TEMPERATURE
 Hypothermia
o Reduce CMR in a temperature-dependent fashion
o Mild hypothermia(32-35℃) ; negliable effect on CMR
o But, in several studies mild hypothermia produce major
protection ; meaningful neuroprotection
o Deep hypothermia(18-22℃) ; highly neuroprotective
o In normothermic brain ; only a few minutes of
complete global ischemia cause neuronal death
o In deep hypothermia before circulatory arrest ; brain
can tolerate over 40 min and completely or near-
completely recover

62. To be Monitored..
 Haemodynamic; CVP,MAP, CPP
 Haematological ; PCV 35-40
 Oxygenation; Above 60mmHg
 Ventilation ; CO2 30-35mmHg
 Temperature;
 -BUSE
 I/O chart
 ICP; keep less than 20mmHg
 EEG-2 parietal electrodes
 Other organ function