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Dr.Sudhakar.

B,
Associate
Professor,
Dept of
Anaesthesia,
DrPSIMS & RF,
CHINOUTAPALLI.

Definition
The perfusion of brain insufficient to provide supply

of O2 & nutrients needed for maintenance of


neuronal integrity and neuronal function

Normal CMRO2 - 5.5 ml / 100 gm / min


Neuronal function utilises 55% - 60% (3.3 ml / 100

gm / min)

Neuronal integrity utilises 40% - 45% ( 2.2 ml / 100

gm / min)

Types
( 1 ) Global Cerebral ischemia
Complete No CBF
Seen in cardiac arrest
Most vulnerable regions of brain
-hippocampus , Cerebral cortex
- Incomplete - CBF
Seen in hypotension, shock
( 2 ) Focal Cerebral ischemia
occlusion of a single cerebral artery

availability of O2 & glucose

ATP depletion

Anaerobic metabolism of glucose

lactate

ischemic damage
free radical formation

Lipid peroxidation of cell membranes

release of excitatory neurotransmitters

Neuronal cell death

immediate
NMDA

Influx of Ca+2, Na+ , Cl- , H2O

Cellular edema
Cell membrane lysis
Cell death

delayed( 24 72 hrs )
NMDA
Ca+2 influx

phospholipases
proteases

Free radical & FFA

Cell death

Cytosolic Ca+2 due to


ATP
- Failure of Na+/ K+ ATP ase ion pump
intracellular Na+ & Cl extracellular K+
-Influx of H2O
-Cellular edema
-Membrane depolarisation
-Opening of voltage sensitive Ca+2 channels.
ATP
-Failure of plasma membrane Ca+2 ATP ase pump
Ca+2 pumping out of cell
ATP
- activity of Ca+2 ATP ase pump in endoplasmic reticulum
(which Ca+2 in cytosol & in endoplasmic reticulum
NMDA receptor mediated opening of Ca+2 channels
Loss of Na+ gradient , an energy source of Na+ Ca+2 exchanger
which pumps Ca+2 out

Ca+2

phospholipases A,A2,C
mitochondrial Ca+2
proteases

(calpains)
Hydrolysis of membrane
mitochondrial dysfunction
Phospholipids
& damage
essential

protein
FFA release
breakdown
PG , LT cerebral edema
TxA2 platelet aggregation
ischemia
Free radicals lipid peroxidation
Mitochondrial & cell
membrane damage

damage

NECROSIS
APOPTOSIS
- Milder ischemia

- more severe ischemia

-Primary form of cell death -primary form of cell death


in penumbra
in the core
-Orderly programmed cell
death, requires energy

- cell disintegration

-Can be modulated &

- cant be reversed

reversed

CLINICAL ASPECTS OF ISCHEMIA


Most vulnerable part brain
Loss of consciousness within 15 sec of cardiac

arrest

Brain phosphocreatine to low levels in 1

minute

ATP , Glucose to low levels in 4 5 minutes


Critical CBF 18 20 ml /100 gm / min
Isoelectric CBF 15 ml / 100 gm / min
Metabolic Failure CBF 10 ml / 100 gm / min
Critical CPP 50 mm Hg
Critical PaO2 30 -35 mm Hg in healthy awake

PATIENTS WHO WOULD BENEFIT


FROM

CEREBRAL PROTECTION

Patients who require resuscitation from cerebral


ischemic damage

ICU patients who have non operative TBI (traumatic brain


injury) such as DAI (diffuse axonal injury) with ICP and
with cerebral edema and candidates for barbiturate coma

Patients who have had cardiac arrest with re


establishment of circulation

Neonatal birth asphyxia

Reyes syndrome and cerebral edema with ICP

Near drowning victims who have


anoxic encephalopathy
cerebral edema
intracranial hypertension

Non hemorrhagic stroke patients who may be candidates

for fibrinolytic therapy and rtPA

Patients who are at risk for cerebral ischemia and

reperfusion Injury

Patients with intracranial volume from tumour, abscess,

hematoma, hydrocephalus, chronic cystic fluid collections

ICP posted for neurosurgery

Patients scheduled for

intracranial vascular procedures such as cerebral


aneurysm coiling or clipping, excision of AVMs & cavernous
angioma
extracranial
vascular procedures such as CEA ( carotid
endarterectomy ), superficial temporal artery MCA bypass

Patients scheduled for clipping / coiling of giant / complex

basilar artery aneurysms

CPB ( cardio pulmonary bypass patients ) at risk for


global ischemia from low flow states
focal ischemia from multiple small emboli

Patients who are at risk for cardio embolic strokes

Patients with AF ( atrial fibrillation )

Patients who are at risk for AF ( > 1 risk factor )


- - CHF ( congestive heart failure ) with EF < 35
% or
FS ( fractional shortening ) < 25
- Hypertension
- Age 75 years
- DM
( diabetes mellitus )

CLINICAL CEREBRAL PROTECTION


Avoid hyperthermia
Avoid hyperglycemia & hypoglycemia

AVOID GLUCOSE CONTAINING SOLUTIONS unless the


patient is hypoglycaemic or at risk for hypoglycaemia
Current recommendation is to keep serum glucose <
150 mg / dl

Avoid hypoxia & hypercarbia


Avoid hypotension

SBP < 90 mm Hg or MAP < 70 mm Hg or CPP < 50 mm Hg


Prompt correction of acidosis & electrolyte imbalance
Avoid high hematocrit and hypercoagulated state

hemodilution to hematocrit of 32% - 34% CBF by


viscosity & improving O2 delivery
but excessive hemodilution O2 carrying capacity of blood

Normalisation of ICP

- Head elevation to 30 in neutral position


- Mannitol 0.5-1 gm / kg
- Furosemide 0.25 0.5 mg / kg diuresis
- Limited fluid restriction to maintain normal CVP
- Moderate hyperventilation to PaCO 2 of 25 30 mm Hg
- CSF drainage via ventriculostomy
- Barbiturate coma in patients unresponsive to these

RECOMBINANT TISSUE
PLASMINOGEN ACTIVATOR
The only recognised treatment to improve

outcome in ischemic stroke

It should be given to patients within 3 hours of


onset of ischemic stroke
( class 1, level of evidence A )
Recent update says that it can be given in a

few subset of patients upto 4.5 hours after


onset of symptoms
( class 1, level of evidence B )

CRITERIA FOR DETERMINATION OF


PATIENTS ELIGIBILITY FOR rtPA
Diagnosis of ischemic stroke causing measurable

neurologic deficit
The neurological signs shouldnt be minor &

isolated and shouldnt be clearing spontaneously


Symptoms of stroke shouldnt be suggestive of SAH
Caution in patients who has major deficits
No history of previous intracranial haemorrhage

No arterial puncture at a major non compressible

site in previous 7 days

No major surgery in the previous 14 days


No gastrointestinal / genitourinary haemorrhage in

the previous 21 days

No myocardial infarction or head trauma or prior

stroke in the previous 3 months

B.P. < 185/110 mm Hg


Blood glucose > 50 mg/dl

No evidence of active bleeding or acute trauma

(fracture) on examination

Not taking an oral anticoagulant or

if anti coagulation is
taken, INR 1.7 for 3 hours window

If heparin is taken in the previous 48 hours,

normal aPTT is must

Platelet count > 1,00,000/cc


No seizures with post ictal residual neurologic

deficits

CT doesnt show multi lobar infarction

(hypodensity > 1/3 of cerebral hemisphere)

Additional exclusion criteria for patients


eligible for rtPA between 3 and 4.5 hours
Patients older than 80 years
All patients receiving oral anticoagulants

irrespective of INR
Baseline NIH (National Institute of Health )

Stroke Scale Score > 25


Patients with history of both stroke & diabetes

Recommended Regimen for rtPA


i.v. rtPA 0.9 mg/kg ( maximum dose 90

mg ) over 60 minutes
10% of the dose as bolus over 1 minute

Admit the patient to an ICU/ITU/stroke

unit for monitoring

Perform neurologic assessment

every 15

minutes during infusion


every 30 minutes
thereafter for next 6 hours
every 60 minutes
till 24 hours after treatment

Measure the B.P.

every 15 minutes for the first 2


hours
every 30
minutes for the next 6 hours
every 60 minutes till 24 hours after
treatment
the frequency of B.P. measurements
if SBP > 180 mm Hg / DBP > 105 mm Hg
give anti hypertensive drugs to maintain B.P. at
these levels

Discontinue the infusion, if the patient develops

severe headache
acute
hypertension
nausea / vomiting
and obtain an emergency
CT scan
Delay insertion of nasogastric tubes / indwelling

bladder catheters / intra arterial pressure catheters


Obtain a follow up CT scan at 24 hours before

starting to administer anti coagulants or anti


platelet drugs

HYPOTHERMIA
Mild - 32C - 35C
Moderate - 26C - 32C
Deep - 18C 25C

Temperature Coefficient (Q10 )

The factor by which CMRO2 changes for every


10C change in temperature
Q10 between 37C & 27C 2.2-2.4
between 27C & 17C 5
between 17C & 7 C 2.2-2.4
For each C in body temperature, CMRO2
by 7%

Mechanism of neuroprotection
in CMRO2
Delayed ischemic / anoxic depolarisation
Metabolism downregulation
Preservation of ion homeostasis
Ca+2 influx
excitatory amino acid release
Preservation or reduction of damaging secondary

biochemical changes
Preservation of protein synthesis & blood brain
barrier
Prevention of lipid peroxidation
in edema formation
Neuroprotection of white matter
Modulation of inflammatory response & apoptotic
cell death

At present mild hypothermia is recommended


only for
Post cardiac arrest survivors
Neonatal birth asphyxia
which has shown improved survival rates &
neurologic outcomes

Induced hypothermia after TBI, stroke, CPB,

intracranial aneurysm surgery may have beneficial


effects for both
ICP & neuroprotection, but clinical trials didnt
justified
its use in these circumstances

A subset of patients has shown more responsive to

therapeutic hypothermia in clinical trials


- age < 45 years
- severe TBI with GCS 4-7 on admission
- ischemic stroke when given with re establishment
of cerebral perfusion

Deep hypothermic circulatory arrest ( 18C -

25C ) is useful in certain situations


- repair of complex congenital heart disease
- adult thoracic aortic aneurysm surgeries
- giant / complex intracranial aneurysm
surgeries

Complications of
Hypothermia
1.Cardiovascular
complications

3.Metabolism
-

myocardial depression
- dysrhythmia including
ventricular fibrillation
-hypotension
- inadequate tissue
perfusion
- ischemia
2.Coagulation
- thrombocytopenia
- fibrinolysis
- platelet dysfunction

- slowed metabolism of
anaesthetic agents
- neuromuscular
blockade
- protein catabolism

4.Shivering
-

O2 consumption
CO2 production
cardiac output
arterial O2

ANAESTHETICS & ADJUVANT DRUGS


Intravenous Anaesthetics
Barbiturates
used for treating cerebral edema that doesnt

respond to other approaches


also indicated for ICP / seizures unresponsive

to other treatment

TPS
in CMRO2 upto 55% - 60%
CMRO2 more than CBF
Also CBV & ICP
preserves CO2 reactivity
Inverse Steal Phenomenon
dosage 3-5 mg/kg every 5-10 min

Upto total of 15-20 mg/kg for EEG burst


suppression
Caution avoid hypotension

Large doses causes duration of action

the extent of cerebral injury in focal ischemia

in animal models
Not shown to improve outcome after global

ischemia from cardiac arrest

Protective mechanisms
GABA agonism
Free radical scavenging
membrane lipid peroxidation & damage
NMDA antagonism
Ca+2 channel blockade
Maintenance of protein synthesis

PROPOFOL
2,6 di iso propyl phenol
CBF more than CMRO2 (possible direct

vasoconstriction) thus ICP

more hemodynamic suppression than

barbiturates
So maintain MAP & CPP

caution while using hyperventilation


causes minimal interference with

electrophysiologic monitoring
( SSEP , MEP ,
BAEP )
So it is a favourable anaesthetic in neurosurgery

ETOMIDATE
Short acting imidazole
CMRO2 by 50%,CBF & ICP
CO2 reactivity preserved
Maintains cardiovascular stability and CPP
Causes adrenocortical suppression for upto 24

hours by inhibition of 11 hydroxylase

Also may cause myoclonic activity & seizures


Experimental studies showed that brain

infarct size occurs in some cases

BENZODIAZEPINES
CMRO2 & CBF but slight in ICP
preserves CO2 reactivity
inhibitory GABA neurotransmission
also has anticonvulsant, amnestic & anxiolytic properties
Caution for avoiding excessive sedation in patients at
risk for ICP due to hypoventilation induced hypercapnia
DEXMEDETOMIDINE
Sedative, analgesic, anxiolytic, & sympatholytic
no respiratory depression
MAC for inhalational anesthetics
found to be neuroprotective in animal models of focal
ischemia
also found to CBF without altering CMRO2 ,which is not
observed in humans

KETAMINE

- a phencyclidine derivative
- CBF, thus ICP
But unchanged or slight in CMRO2
- abolishes autoregulation
- a non competitive NMDA receptor antagonist.
LIDOCAINE

- Na+ channel blocker


- at low conc. it CMRO2
At higher conc. it causes seizures
After pentobarbital induced isoelectric EEG , CMRO2 by
another 15%-20%
- blunts hemodynamic response & ICP response to intubation
- improved neurologic recovery in animals
No human trials proved it
- 1.5 mg/kg- ischemic damage in animals
Inconsistent human studies

INHALATIONAL ANESTHETICS
Cerebrovasodilators

Therefore CBF & thus ICP


This is attenuated by prior hyperventilation
CMRO2

Thus uncouples CBF & CMRO2


Impairment of autoregulation is seen
preserves CO2 reactivity
Ischemic preconditioning

Animal models have shown that this is due to proteins


formation that damage & repair.
- not induced clinically in humans

Nitrous oxide
CBF, CMRO2 & ICP

But this can be attenuated by hypocapnia, prior


administration of barbiturates, opioids,
benzodiazepines, propofol
32 times more soluble in blood than N2 ,

so it diffuses into air containing body


can enlarge an air embolus

cavities and

avoided in

- Pneumocephalus
- Any surgical procedure within 2 weeks of a
craniotomy in which N2O was used.

ANTICONVULSANT DRUGS
Seizures ischemic effects by in CBF, CMRO2 ,

intracellular Ca+2 during seizure activity


For seizures

Diazepam -2-20 mg
Midazolam - 1-5 mg
TPS - 25-100 mg
Pentobarbital - 100 mg

OTHER PHARMACOLOGICAL
APPROACHES
Calcium channel blockers

Nimodipine
the incidence & severity of vasospasm after
aneurysmal SAH
By blocking Ca+2 influx into vascular smooth muscle &
preventing its hypercontraction
oral route only 60 mg every 4 hours for 21 days
Caution against hypotension
i.v. route should not be given because of life threatening
adverse events & death
Nicardipine
i.v.form
ischemic damage in animal studies but not shown
benefit in clinical trials

Magnesium
Ca+2 influx into cells by blocking channels &

pathways in addition to blockade of voltage


sensitive Ca+2 channels
Blocks neurotransmitter release
Blocks NMDA receptors non competitively
Has shown neuroprotection in different models of

cerebral ischemia
Clinical trials are underway

Glutamate receptor antagonists


No clinical benefit has been demonstrated in human studies.
Non competitive NMDA receptor antagonists like

- Dizocilpine
- Magnesium
- Xenon
Glycine binding site antagonism with

- HA-966
- 7- chlorokynurenic acid
AMPA receptor antagonism with

- NBQX ( 2,3 dihydroxy 6-nitro 7-sulfanoyl benzoquinazoline )

Sodium channel blocking drugs

- Riluzole
- Lamotrigine
Both es glutamate release during ischemia
Clinical trials are underway

Tirilazad

- Lipid soluble 21-amino steroid


- Lipid antioxidant
free radical formation & lipid peroxidation
- Animal studies showed protection only when given before
ischemic event
- No clinical studies proof

Free radical scavengers

- under investigation
Superoxide dismutase
Deferoxamine
Vitamin E
Mannitol
Glucocorticoids
Nitric oxide
Erythropoeitin

- Produced in brain after hypoxic or ischemic insults


- Asialo EPO non hemopoeitic analog
blood viscosity that doesnt exacerbate ischemic injury

Anaesthesia duration & depth


Minimising the duration of time during which

patient is deeply anesthetised may neuronal


damage by attenuating neuronal apoptosis

A growing body of evidence indicates that

cumulative deep anaesthesia time is an


independent predictor of post operative
morbidity & mortality in adult patients

Thank you