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  When brain is deprived of adequate blood flow  ischaemia 
leading to neuronal cell death
 Ischaemia  lasting only few minutes  resulting neuronal death
usually delayed by hours or days
 Biology of the cerebral cell death after global cerebral ischaemia
follows the pattern of delayed cerebral cell death that follows stroke,
TBI, and other forms of hypoxic/toxic brain injury

1. Rosen’s Textbook of Emergency Medicine. 8th edition

2. Fukuda S, Warner D.S.. Cerebral protection. British Journal of Anaesthetisia. 2007
  Neuroprotection  treatment initiated before onset of
ischaemia, intended to modify intra-ischaemic cellular dan
vascular biological responses to deprivation of energy supply
 tolerance of tissue to ischaemia ↑  improve outcome
 Neuroresuscitation  treatment after the ischaemia  to
optimizing reperfusion

1. Rosen’s Textbook of Emergency Medicine. 8th edition

2. Fukuda S, Warner D.S.. Cerebral protection. British Journal of Anaesthetisia. 2007
 Response due to ischaemia and hypoxia
 Up-regulate expression of genes contributing to apoptosis
and inflammation
 Inhibition of protein synthesis
 Sustained oxidative stress
 Neurogenesis

1. Rosen’s Textbook of Emergency Medicine. 8th edition

2. Fukuda S, Warner D.S.. Cerebral protection. British Journal of Anaesthetisia. 2007
 Return of Spontaneous Circulation
 Cardiac resuscitation  first priority in cerebral resuscitation
 Degree of brain injury  depend of both “downtime” / time
before CPR initiation and relative ischaemia during CPR
 CO during optimal standard closed chest CPR  20/30% of
normal

Rosen’s Textbook of Emegency Medicine. 8th edition

Rosen’s Textbook of Emegency
Medicine. 8th edition
Rosen’s Textbook of Emegency
Medicine. 8th edition
The
ischemic
Cascade
Ischemia:
complete,
incomplete,
global,
focal
MONRO KILLIE DOCTRINE
 Brain protection technique similar with
Neuroanesthesia technique
 A= Clear airway
 B= Breathing (Control ventilation)normocapnia or slight hypocapnia
 C= Circulation (Avoid high increase or decrease of BP, avoid increase of cerebral
venous pressure, fluid management)  normotension, normovolemia, iso-osmoler,
normoglycemia.
 D= Drugs ( Avoid drugs & anesthesia technique will increase ICP), give drugs have
brain protection effect.
 E= environment (temperature control, mild hypothermia, avoid hyperthermia)
 Hypotension
 Oxygen delivery  requires high cerebral perfusion pressure, low
cerebrovascular resistance (CVR), and adequate blood oxygen
saturation
 Hypotension  can dangerously lower cerebral perfusion pressure
 Low arterial pressure  iv volume administration and vasopressors
 Elevated arterial pressure  provide sufficient CBF , hypertension
should not be treated in the post resuscitation period (diastolic ≤120
mmHg)

Rosen’s Textbook of Emegency Medicine. 8th edition

  CO2  potent vasoactive
 Lowering of the arterial CO2 partial pressure (Paco2) by
hyperventilation results in rapid reduction of CBF  may transiently
abort brainstem herniation for patients with ↑ ICP
 When ICP is not elevated  vasoconstriction and increaed CVR
caused by hyperventilation  potentially dangerous reductions in
CBF
 Ventilation to maintain a Paco2 of 35-40  safe and appropriate

Rosen’s Textbook of Emegency Medicine. 8th edition

  Normal arterial oxygen saturation  maintained after
resuscitation from cardiac arrest  because injured brain
may not be able to compensate for hypoxia
 Normoxia or mild hyperoxia (PaO2 of 80-120 mmHg with
oxyhemoglobin saturation percentage maintain > 90%) 
maintained through use of the lowest fraction of inspired
oxygen (FrO2) possible

Rosen’s Textbook of Emegency Medicine. 8th edition

Hypothermia – Low Normothermia
 Maintenance of Body Temperature
 Hypertermia (or fever) exacerbates brain injury and worsens
neurologic outcome
 Body temp ↑  increases cerebral metabolic demand by 8-13% per
ºC, escalates glutamate release, increases oxygen free radical
production, and increases cytoskeletal and BBB breakdown with
increased vasogenic edema
 Treated with antipyretics, circulating air or water cooling
systems, or evaporative cooling via water mist and fans

Rosen’s Textbook of Emegency Medicine. 8th edition

 Resuscitative Mild Hyperthermia
 Hypothermia  glutamate release , metabolic demand, free radical
formation, and production of inflammatory cytokines  ↓↓↓
 May protect the brain from pragrammed neuronal cell death
 Techniques used to induce hypothermia  traditional and
advanced surface cooling, adminitration of ice-cold saline, and
endovascular cooling
 Cooling may be initiated before ROSC

Rosen’s Textbook of Emegency Medicine. 8th edition

Plasma Glucose Concentration
 Avoidance of hyperglycemia : < 150 mg%, Maintained 100-
150 mg%, assayed every 2 hours
 Hyperglycemia associated with worsened outcome following
stroke or neurotrauma.
 Normoglycemia may protect neuron (decrease intracellular
lactic acidosis, decrease membrane permeability, reduced
edema of endothelial cells, neuroglia, neuron).
 Profound hyperglycemia (>500 mg/dL)  decrease in
intracellular pH, increases brain lactate levels, and increases
neuronal loss
  Seizure activity  increase brain metabolism by 300-400%
 Common therapeutic agents include benzodiazepines, phenytoin,
and barbiturates  been considered as specific therapy for cerebral
ischaemia  antagonism of excitatory amino acids, sodium channel
blockade, or effects on cerebral metabolism

Rosen’s Textbook of Emegency Medicine. 8th edition

 Pharmacology Method
Neuroprotection Properties of iv Anesthetics

Barbiturate
  CMRO2
  ICP
 Ca influx 
 Na channel block
 Free radicals inhibition formation.
  Extracellular lactate, glutamate, aspartat
Neuroprotection Properties
of Volatile Anesthetics
 Neuroprotection in term of anti-necrotic and
anti-apoptotic effect
 Increase CBF in ischemic region.
 Reduction of functional CMR
 Suppression of convulsions

Werner C. AOSRA Nov 2003, WCA, April 2004. ESA June 2004.
Neuroprotection properties of volatile
anesthetics
 Isoflurane, sevoflurane, desflurane produce maximum cerebral metabolic
suppression (2 MAC)  correct for imbalance between oxygen supply and
demand.
 Inhibition of lactic acidosis and excitatory neurotransmitter release
 Prevention of pathological Na+, Ca2+ influx.
 Inhibition of lipid peroxidation.
 Reduction of free radical formation.

Werner C. AOSRA Nov 2003

Isoflurane
 Isoflurane only transient protective against a severe focal ischemic
insult.
 Isoflurane did not inhibit post ischemic neuronal apoptosis.
 Conclusion: Isoflurane have not brain protection effect.

Werner C. AOSRA Nov 2003, WCA 2004, ESA 2004.

Cottrell JE: WCA 2004, ESA June 2004
Kawaguchi et al. Anesth Analg 2004
Warner DS.Anesth Analg 2004
Sevoflurane

 Sevoflurane improves neurological outcome following

incomplete cerebral ischemia in rat.
Werner C et al.Br J Anesth 1995;83
 Isoflurane delay but does not prevent cerebral infarction in rats
subjected to focal ischemia.
Kawaguchi et al. Anesthesiology 2000;92
 Sevoflurane provides sustained anti necrotic and anti apoptotic
effect.

Engelhard et al. ASA Annual meeting 2003. Abstract A 740

 Sevoflurane provides sustained brain protection durn moderate
ischemic challanges.
 These effect are related to anti-excitotoxicity and a decrease in
apoptosis.
 These effect are additionally mediated by a pharmacological
preconditioning effect.
 The brain protective effect of volatile anesthetics are not yet
confirmed in adequate clinical trial.
Desflurane
 Desflurane was associated with more cerebral vasodilatation and higher
ICP than sevoflurane and isoflurane at normocapnia
Holmstrom A, Akeson J. J Neurosurg Anesthesiol 2004;16:136-43

 At 1 MAC CBF with desflurane was 16% higher than with isoflurane and
24% greater than with sevoflurane
Holmstorm A, Rosen I. J Acta Anaesth Scand 2004:48:400-4.)
Lydocaine

 Blocking Na influx
 Reduce post necrotic injury
 Truncates ischemic damage in the penumbra by blocking the apoptotic
cell death pathway that involve cytochrome

 lydocaine have brain protection effect.

 Effect of Anesthetics on Physiological Responses
and Ion and Metabolite Levels
Anoxia NMDA/AMPA
Protect Improve Improve Improve Protect
+ +
Response NA ATP Ca Response

Thiopental (600 μM) Yes Yes No/Yes1 Yes Yes

Midazolam (100 μM) Yes - Yes Yes -
Propofol (20 μg/ml) No Yes Yes Yes No
Lidocaine (10 μM) Yes Yes Yes No -
Isoflurane (1,5%) No No No No -
Sevoflurane (4%) Yes Yes Yes Yes -
Etomidate
3 μg/ml No No No - -
30 μg/ml No Yes No - -
Nitrous oxide (50%) No No No No -

1Worsens ATP after 3.5 minutes of anoxia:

improves ATP after 10 minutes of anoxia.
Cottrell JE. ESA, 2004,LISBON