Deliberate Hypothermia (PART 2)

TEMPERATURE  MANAGEMENT:(1,4,5)


Rapid cooling is necessary if core temperature must be rapidly although body temperature typically decreases more than one degree C during the first hours of general anesthesia.


Methods use to reduce brain temprature during animal experiments include packing ice,fanning,partial immersion in cold water,nasopharyngeal cooling and cardiopulnary bypass(CPB).


Rapid reduction of core temprature for mild or moderate hypothermia can be facilitated by administration of refrigerated intravenous fluid,circulating water mattresses ,forced aircooling and extracorporal means.


Intravenous administration of refrigerated (1-6) degrees C 5% albumen 5cc/kg during a period of 3 to 5 minutes,after surface cooling to 34 degress C reduces core temperature by approximately 0,6 degrees C.


To achieve maximal effectiveness,refrigerated fluids must be administered rapidly (100 ml/min) to avoid heat gains in standard intravenous tubing.


In controlling body core temperature, forced air cooling has the advantage of cooling a large skin area but seems to be even more effective when used in combination with a circulating water mattress.


In a series of eight patients with severe trauma brain injury(TBI) a heat exchanger was connected by a pressure controlled roller pump to a percutaneously introduce double lumen canule in femoral vein.


Cooling was initiated at a cooling speed of 3,5 degrees C/hour and hypothermia was maintained with 0,1 degree C at 32 degrees C brain temprature for 48 hours. 


Using this technique a brain temprature of 32 degrees C,was achieved within 113 minutes(moreless 81 min) after
cooling began.


Although this invasive technique and platelet count decreased during treatment no clinical bleeding complications or problems resulted from extracorporal circulation.


SURFACE COOLING BY USE OF TUB TECHNIQUE :


After induction and intubation,when vital signs of anesthetized patient are stable,the patient is immersed in  cold water keeping the chin and hands above the water level.


When the vital signs again stabilize ice cubes are added to the water. Cooling usually taken 30-6o minutes.The patient is kept in the ice water until body temperature has drops to about 40% of the desired value,since after the patient removed from the tub and transfered to the operating table,the temperature continues to drop(drift),frequently by 3 to 4 degrees C.


If the desired temprature is 28 degrees C the patient is removed from the ice water when his temprature is 32 degrees C.


As the body temperature drops, the concentration of anesthetics is gradually reduced until their administration stopped at body temperature at 28 to 30 degrees C. From this point on, no further administration of anesthetics is necessary. But controlled hyperventilation with oxygen continues for the duration of surgery.The pupils are ordinary dilated the during hypothermic period.


The patient is removed from the ice water.Then he is thoroughly dried with bath towels and placed on water filled mattresses for rewarming.


If the patient move spontaneously while being rewarmed,a mixture of 50% N2O and 50% O2 is usually sufficient to keep him quiet.


During rewarming, reflexes and spontaneous movement reappear at about 31 degrees C and conciousness return at 32 to 34 degrees C.


Extubation is carried out when respiration are adequate.


The tympanic or rectal temperature is monitored for at least 24 hr postoperatively to ensure that temprature is maintained at about 36,5 degrees C.


Also the patient is observed carefully during this period for any signs of shock or reactive hyperthermia.


LOCAL REFRIGERATION ANALGESIA :


This method can be useful for handling severely traumatilimbs that require amputation.


1.The tissue are chilled for about 1 hour then a torniquet is 
   applied.
   The torniquet must be tight enough so the tissues distal 
   to the torniquet are blanched rather than congested.
2 The limb is placed in cracked ice and cooled for 2-3 hr,
   depending on whether it is an arm or a leg.
   The limb is placed so that the melting ice will drain away 
    from the bed.
3.The patient is placed on the operating table and the limb 
    is dried. The analgetic effects will last for 1 hr.
4.When the larger vessels have been tied the torniquet is 
    released and adequate hemostasis is obtained.
5.Ulceration of tissues will not occur if actual freezing and 
   excessive pressure are avoided.
6.Disadvantages.The labor and time involved in preparing 
   the patient for surgery.


INDICATIONS OF HYPOTHERMIA :


a.Aneurysmectomi
b.Carotid artery surgery in the neck.
c.Surgery of vascular tumors such as meningioma.
d.Management of severe brain injury especially brainstem 
   injury with high fever,coma,tachycardia,tachypnoe and 
   rigidity,acute cerebral vascular accident and ruptured 
   intracranial aneyrysm.


COMPLICATIONS :


Prolonged hypothermia can cause mask infections and coagulopathies and sign of cerebral compression.


Deep hypothermia causes myocardial depression,hypoten-
sion,arrythmia and cardiac arrest and potentially causes multifocal ischemia from reduced microcirculation and post operative shivering.


SUMMARY :


For patients at risk for ongoing brain injury,patient temperature should be monitored and aware that brain temprature might be greater.


The increase of systemic or brain temperature should be treated promptly and vigorously, because it worsen neurologic outcome after brain injury.


In TBI patient selection should focus on younger patients with GCS of 5 to 8,and ICPs between 20 and 40 mmHg because beneficial effect with hypothermia may be achieved end less effective for GCS of 3-4.


Considering of adverse effect of hypothermia patients who need extracranial surgery should be kept normothermic.


REFERENCES :


1.Donner Andrews and Illievics M Udo:Hypothermia ;
  Fleischer A Lee et a Problems in Anesthesia,Cerebral 
  Protection,Resuscitation and Management,vol 12, No.4 
  Lippincott Williams &Wilkins London.2000,pp.461-3.


2.Stone D.J, Bogdonoff L david: Anesthesia for intracranial 
   vascular surgery Stone D.J,Sperring J.Richard; The Neuro 
   AnesthesiaHandbook,Mosby,St.Louis,Baltimore,Boston,
   1996,pp.350-1.


3.Lam M Arthur: Cerebral Aneurysma,Anesthetic considera-
  tion;Cottrell E. James,Smith S. David:Anesthesia and 
  Neurosurgery,4 edit,Mosby,St Louis,London,Philadelphia  
  2001,pp 389-90.


4.Warner S.David:Effects of Anesthetic agents and tempe-
   rature on the injured brain;Albin S Maurice:Textbook of 
   Neuro Anethesia with Neuro surgical and Neurosciences 
   Perspective,Mc Graw Hill USA,1997,pp 604-6.


5.Snow C.John: Hypontensive technique and Induced 
   Hypothermia, Manual of Anesthesia,first edit,Little Brown 
   Company,Boston,Tokyo.1978.pp.246-51.


6.Doyle W Pattrick &Gupta K Arun: Mechanism of Injury and 
   cerebral protection; Matta F Basil; Neuro Anesthesia and 
   Critical Care,Greenwich Medical Media Ltd,London ,2000
   pp.45-46.


7.Collins J.Vincents: Temperature Regulation and Heat 
   Problems; Collin J,V Physiologic and Pharmacologic  Bases 
   of Anesthesia,Williams & Wilkins Baltimore,Philadelphia,
   1996.pp.316-17.

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Deliberate Hypothermia (PART 1)

INTRODUCTION:(1,2,6,7)


Core central temperature is defined as the temperature
blood perfusion vital major organ system.


Nasopharyngeal and esophageal temperature are more representative of core temperature. 


Core temperature varies not only interindividually and diurnally but also between different parts of the body.

In unanesthetized persons thermoregulatory response is
not triggered by temperature range of 0,2 degree C.


Physiologic termoregulatory response normally triggered by hypothermia.Therefore if normothermia is not actively maintained general anesthesia may lead to unintentional low body temperature.


Perioperative hypothermia commonly results from anesthe-
tic induced inhibition of the thermoregulatory as well as a
cold ambient environment in the operating room and the
heat loss owing to surgical exposure of tissue.


Anesthetized persons often behave like poikilothermia until the core temperature approaches a new setpoint for thermoregulation.


Patients at greatest risk for perioperative hypothermia include elderly patients burn patients, neonates and patient with spinalcord injuries.Hypothermia occurs when heat loss exceeds heat production.


Clinical dose of general anesthesia decrease the thresold for response to hypothermia from approximately 37 degrees C (normal) to 33 degrees to 35 deg C).


Anesthetized patients where core temperature exceeds these values are usually poikilothermic and do not actively respond to thermal pertubations.


Hypothermia with shivering is a common post operative finding will increase oxygen consumption by as much as 400%.will raise cerebral metabolic rate for O2(CMRO2)
and possibly intra cranial pressure(ICP) and myocardial ischemia in patient with coronary artery disease.


Even mild hypothermia can prolonged emergences from general anesthesia. But deliberate mild/moderate hypothermia may be used intra operatively to protect the brain from ischemic injury.In a recent poll taken from members of The American Societry of Neurosurgical Anesthesia and Critical Care 40% clinician practiced induced hypothermia in patients undergoingcerebral aneurysma surgery.


Physiologic consideration:(3,4,5)
1.Effect on metabolism:
   a.When blood is cold the oxygen dissociation curve shifts 
       to the left.
    b.The rate of oxygen consumption falls as body tempera-
        ture falls (but tissue oxygen need does not fall in a 
        direct ratio).
    c.Essential oxydatives enzymes are not inactivated by 
       hypothermia.
2. Effect on respiration :
    As the body temperature falls the solubility of CO2 in  
    the blood increases.
3. Effect on the heart :
     The heart rate,coronary blood flow and oxygen uptake  
     of the heart are decreased by 50% when the body temp-
     rature is 25 degrees C.    
     ECG features : 
         The QRS complex lengthen,the PR interval prolonged 
         and there is elevatio of the early part of the ST 
         segment(the precursor of venrtricle fibrillation). 
         The atrium frequently begin to develops flutter or 
         fibrillation at temperature below 30 degree C and the 
         ventricel usually fibrilate below 28 degrees C.
4.The general circulation changes :
   a. Cerebral,renal and splancnic areas blood flow decrease
       as body temperature decrease.
    b.The mean arterial pressure(MAP) is decreased by 5% for 
        each degrees centrigrade below 37 degrees C.
5.The Central Nervous System (CNS):
    a. CMRO2 decreases to 50% of normal with hypothermia 
         to 30 degrees C and 25% of normal at 25 degrees C, 
         15% at 20 degrees C and 10% at 15 degrees C .
         Period of circulatory arrest tolerated at normother-
         mia in only 4 to 5 minutes but it doubles for every 8 
         degrees temperature reduction.
          Period of tolerated circulatory arrest at 38 degrees C 
          for 4-5 min, at 30 degrees C for 8-10 min, at 25 deg-
          ress C for 16-20 min, at 20 degrees C for 32-40 min, 
          and at 10 degrees C for 64-8o min.
       b.Cerebral blood flow(CBF) decreases by 7% for each 
          degrees centrigrade below 37 degress C.
       c. The Cerebrospinal fluid (CSF) pressure and CSF 
            production rate decrease.
       d. Cortical function is decreased so there is retrograde 
            amnesia for events happening under hypothermia.
6.Effect on renal function:
   a.Hypothermia protects the kidney from adverse effects 
      when the blood supply is occluded during surgery.
   b.The Glomerular Filtration Rate(GFR) and Renal Blood 
       Flow(RBF) are reduced 35% at 25 degress C.
7.Effect on liver function:
    A.Changes in clotting mechanism:

      a.the bleeding time is increased  
      b.the platelet count falls and the postthrombine time        
          to shortened.
      c.clot retraction is poor.

    Hypothermia induced coagulopathy is caused by multiple 
    factors:
    1.Hypothermia reduced platelets count probably from 
       splenic squestration.
    2.It causes a reversible pletelets dysfunction by decreas-
       ing adhesiveness .
    3.It slow down the enzyme mediated steps in the 
       coagulation cascade.
    4.It decreases the metabolism of heparin.

       The dilutional effects of priming solutions with   
       cardiopulmonary by pass(CPB)on factors I,II,V,VII and 
       XII also contribution to difficulty with homeostasis.
       Hypothermia also causes an increase in viscocity 
       leading to sludging of erythrocytes.
   B. Morphine is slow to be conjugated and detoxified in 
       the liver.
   C.The metabolism of barbiturates is impaired.

   D.It is possible that nor epinephrine and tubocurarine 
      could remain undestroyed in areas of vascular stasis and      
      on rewarming, be released  into general circulation.
8.Effect on Acid base balanced:
   a.The buffering capacity of the blood is reduced during 
       hypothermia.
   b.Alveolar ventilation and kidney's ability to regulate acid 
      base disturbances are decreased.
   c.The heart is more sensitive to low blood pH which can 
       increase both its irritability and its tendency to ventri-
       cular fibrillation(VF) therefore the patient should be 
       hyperventilated to raise the blood pH.
   d.The oxygen Hb curve is shifted to the left therefore the 
       Hb has more affinity for oxygen.
    e.On rewarming there is some metabolic acidosis (mostly 
        lactic acidemia).
General consideration :
1.The use of dextrose solution during hypothermia carries 
   risk because dextrose is metabolished very slowly during 
   hypothermia and therefore accumulates in the ECF and by 
   its osmotic effects draws water from cells.
   The extra water delutes the ECF and thus the serum 
    electrolyte.
    But during rewarming dextrose solutions should be admi-
    nistered because the dextrose level will then to fall.
2.The serum potassium tends to be low when pH is high
    (alkalosis).
    The extracellular potassium rises whenever there is    
    tissue anoxia.


9.Effect on anesthetic drugs:

   1.The effect of thiopental are potentiated and prolonged 
      during hypothermia so its use should be restricted be-
      cause thiopental has direct depressant on the myocardi-
       um.
   2.Inhalation agents:
      Hypothermia potentiates the effect the anesthetics 
      drugs and delays their excretion .Therefore as hypo-
      thermia progresses smaller amounts of anesthetics 
      agents are required.
      Halothane is potent vasodilator and N2O is the least 
      toxic of the inhalation anesthetics.
   3.Muscle relaxant :
      Duration of action of muscle relaxant is likely to be 
      increased by mild hypothermia. 
      For example the duration of action of vecuronium is 
      twofold when body temperature is reduced from 36,8 
      degrees C to 34,4 degrees C.   
      Muscle stiffness may be present at 33 degrees C it may 
      remain until rewarming.
      Caution should be remembered during rewarming the 
      action of non depolirizing relaxant may become 
      manifest.
   4.Other drugs:

      The action of atropine is gradually decreased as cooling 
      progresses. Epinephrine retains its activity in the cooled 
      patient at least to 25 degrees C.
      Norepinephrine is less active in the hypothermic patient 
      and remain partially inert until rewarming when it can 
      causes a marked degree of hypertension.
      Neostigmine maintains its action during hypothermia.

      Preoperative administration of digitalis can augment 
      the decreased heart rate during hypothermia.


Mechanism of hypothermia protection:(3,4,6)


Mechanical cooling was first desacribed 1943.          
Hypothermia is non pharmacologic method of reducing CMRO2 causes a significant in cerebral oxygen consumption and has been demonstrated to protect the brain during anoxic condition.



Hypothermia can be protection not only by virtue of its
effect on CMRO2 but cellular and biochemical efects
better explained how hypothermia protect.


Mild hypothermia (34 to 36) degrees C effectively blocks glutamate which massively increased during an ischemic insult are believed to iniate an excitotoxic cascade ulti-
mately resulting in cell death.


Energy faillure is associated with a large influx of calcium
in vitro studies have shown that mild hypothermia reduces calcium influx.


Probably hypothermia cause decrease opportunity for intracellular calcium to accumulate to concentrations sufficient to exert toxic effects.


Hypothermia diminishes membrane bound PKC activity in selectively vulnerable regions of post ischemic brain.


PKC is enzyme involved in regulating neuronal excitability and neurotransmitter release is activated in response to an increase in cytosolic calcium.


Hypothermia also can reduce accumulation of lipid peroxi-
dation products and the consumption of free radical sca-
vengers in ischemic brain. Globus et al have demonstrated that free radical production persist for at least several hours after reperfusion.


The quantity of free radical generated is reduced to almost normal values by moderate hypoyhermia (32-34) degrees C.

Hypothermia can also suppress Nitric Oxyde Synthase activity this is beneficial if Nitric Oxyde or free radical mechanism are germane of pathogenesis of neuronal death.



Possible mechanism for the neuroprotective effect of hypothermia:

1.Reduction of rate energy use for electrophysiology cortical activity.

2.Reduction of extracellular concentration of excitatory amino acids.

3.Attenuating free radical production.

4.Suppressing the post traumatic inflamatory response.

5.Maintanance of high energy phosphate.

6.Prevention of Protein kinace C down regulation

7.Recovery of post ischemic protein synthesis.



The most recent trial concluded that treatment with moderate hypothermia for 24 hours initiated soon after head injury significantly improve outcome at three and sixmonths in those with a Glasgow Coma Scale(GCS) of 5-7.



Mild hypothermia is not associated with cardiovascular and metabolic dearrangement commonly observed at lower temperature.



To be continued

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Brain Ischemia And Protection (PART 2)

BRAIN PROTECTION:(1,2,5)


Cerebral protection implies intervention designed to prevent pathophysiological process from occuring whilst cerebral resuscitation refers to intervention instituted after onset of the ischemic insult in other to interrupt
process. To prevent neuronal death from ischemic or hypoxaemia, two basic strategies can be employed :


Prevention of tissue hypoxia primarily or modification of the event that lead to cell injury and death subsquent to energy failure.


The prevention of tissue hypoxia can be devided into two general categories decreasing tissue O2 demand and increasing O2 supply.


Supplementary pharmacological brain protection includes intervention that increase CBF in the ischemic area,reduced cerebral metabolism and ICP; inhibit lactic acidosis, antagonize excitatory neurotransmitter activity,prevent excessive calcium influx,inhibit lipid peroxidation and scavenge oxygen free radical. Unless normoxia and normotension are maintained the aplication of drugs that antagonizes the process is bound to be ineffective.


Anesthetic agents :


They have been examined for their ability to improve recovery from ischemia the theory being that they reduced neuronal activity and metabolic rate and therefore should reduced energy demand, enhance energy supply and attenuate ischemic damage either inhalation or non inhalation agents.


Volatile anesthetics :(2,5)


Inhalation anesthetic agents may be their ability to suppress cortical electrical activity and thus reduce demands associated with synaptic transmission.


Isoflurane,sevoflurane and desflurane produce comperable and maximum cerebral metabolic depression at end tidal concentration >2 MAC.


They could ameliorate the imbalance between cerebral O2 supply and demand during focal ischemia.


Halothane not usually regarded as a cerebral protectant, provides a similar degree protection to sevoflurane although it results in less metabolism suppression.


In contrast volatile anesthetics have no neuroprotective properties in the setting of global ischemia(GI) and when given after the insult.


Intravenous anesthetic agents :
Barbiturate :(2,5)
Prototype for anesthetic protection against cerebral ischemia ,attributed to
their ability to decrease the cerebral metabolic rate(CMR)thus improving the
ratio oxygen supply to oxygen demand.


More spesifically these agents appear to selectively reduce the energy expenditure required for synaptic transmission. 


Whilst maintaining the energy required for basic cellular function.


Maximum metabolic supression by anesthetics agents can reduce oxygen demands to approximately 50% of baseline values, since the remaining oxygen utilization is required to support cellular intergrity rather than suppressible 
electrical activity.


Barbiturate appear to be particularly protective in conditions of focal ischemia as even though blood flow may reduced, some synaptics transmission continues and its suppression can improve oxygen demand/supply relationship.


Such electrical activity is absent during global ischemia(GI) and studies to date have failed to demonstrate any improved clinical outcome with anesthetic neuroprotection following cardiac arrest.


In comatose patient within the first hour after cardiopulmonary resuscitation high dose barbiturates did not reduce mortality or attenuate neurologic deficits
in survivors component with patients who only received standard intensive care unit treatment.


Thiopental considered to be the gold standard for anesthetic protection produce no change in PO2 or pH when burst suppression EEG was induced.


Propofol :(2,6)


Decrease neuronal activity on the EEG with an accompanying decrease in cerebral oxygen utilization and CBF.


A number of mechanism have been claimed to explain the neuroprotective effects of propofol including reduction of CMRO2,antioxidant activity toward both lipophilic and hydrophilic radicals,activation of gamma aminobutiric acid type.


A receptors and reduction of extracellular glutamate concentation via inhibition of Na channel dependent glutamate release or enhancement of glutamate uptake. 


The oxydative phosphorylation activity of neural mitochondria rapidly deteriorate under ischemic condition leading to energic failure and cell death.


Moreover as consequence of ischemic oxidative stress and mitochondrial calcium overload the mitochondrial permeability transition pore(MPTP) opens allowing the free movement of small molecules weight solution but not of protein,this result in mitochondrial swelling and eventually in rupture of the mitochondria,and release of proapoptotic inducible factor that are normally sequestered and mantain inactivated in the space between the inner and outer mitochondrial membranes.Accordingly drugs capable of preventing increases in mitochondrial membrane permeability such as cyclosporine protect cerebral tissue against ishemia induce damage and propofol capable inhibits the opening of the MPTP.and has been shown documented that propofol is potent free radical scavenger


Etomidate:(2)


Posses similar cerebral metabolic protective effects to the barbiturate but is disadvantaged by its adrenal suppressant effects and ability to cause myoclonic movement. No further reduction of CMRO2 occurs when additional drugs is
administered beyond a dose sufficient to produce isoelectricity.


No benefit in complete global ischemia states.


Opioid,ketamine and benzodiazepine:(2)


Opioids have no neuroprotective properties but they do blunt stress induced responses.


Ketamine is an NMDA antagonist and has been shown to be protective in animal models of ischemia.


While the benzodiazepine decrease CBF and CMR these effects are less impressive than with the intravenous anesthetic agents.


These drugs are not generally thought to be useful neuroprotective agents.


Non Anesthetic agents :


Channels blockers :(2,3,5)


Ca channels blockers as cerebral protective is presumed because of their ability to reduce calcium influx across plasma and mitochondrial membrane.


Proposed mechanisms of its cerebral protection include cerebral vasodilatation,prevention of vasospasm,reduced calcium influx,and modulation of FFA metabolism.


Cacium channel antagonist have been successful in treating patients with subarachnoid hemorrhage and and though they were thought to produce their effects by ameliorating vasospasm they are strongly recomended along with
hypertension, hypervolemia and hemodilution to treat vasospasm.


A recent large clinical study of the efectiveness of blockers of the voltage sensitive calcium channel(nimodipine) after stroke was discontinued because of higher mortality in the nimodipine group and clearly nimopdipine can not be recomended subsequent to cerebral ischemia.Indeed during ischemia and anoxia calcium channels are already inhibited and direct protection of neuron with nimodipine was not observed in vitro preparations.


However magnesium and cobalt are non selective antagonist at all types of voltage sensitive and NMDA activated channels that are involved in calcium
influx into neurons and this may account for their documented neuroprotective effects. Other calcium antagonist have been reported to improve ischemic
lesions namely isradipinie,S emopamal and RS-87846(a Natrium/Calcium channel modulator)but their neuroprotective efficacy and mechanism of action are
as yet not fully established.


Blocking sodium influx during anoxia and ischemia has been shown to improve recovery both in vivo and in vitro.


The neuronal depolarization during ischemia leads to massive flux sodium into neuron and potassium out of the neuron.Blocking sodium influx delays and attenuates depolarization.


Lidocaine has improves recovery by reducing anoxic sodium influx during anoxia at concentration that do not block sodium channels under normal condition.


In addition it also reduces ionics leaks i.e.Na+ inlux and K+ efflux and this reduces NaKATP ase pump energy requirement.


Lamotrigine and BW619c89 also being examined for their protective efficacy.


Fosphenytoin has shown positive results and is in phase III clinical trial.


Enadoline is a new opioid with Na+channel blocking properties under investi-gation.Other Na+ channels blockers are the local anesthetics agents QX-314 and OX-222 which have shown good in vitro but again,human studies awaited


Excitatory amino acids antagonist:(2,3,5)


Excitatory amino acids are implicated in damaging cascade following ischemia,trauma,and epilepsy.


Although blockers of NMDA and AMPA glutamate receptors have improved recovery in vitro and in vivo in a number of preparations, the results of clinical trials have been disapointing.


Apparently these agents have toxicity in and of themselves and may cause neuronal damage. Indeed clinical trials with some of these agents have been terminated early because of adverse outcome.


Non competitive NMDA receptor antagonists include ketamine,dizocilpine(MK 801),aptiganel,dextromethorphan,dextorphan,and magnesium.


Ketamine has been shown to improve cognitive function and dextromethorphan has been shown to improve neurologic motor function and decrease regional odema formation. But the clinical development of the antitussive agents dextromethorphan and dextrophan was also terminated because of side effects such as hallucination,agitation and sedation.


Dizocilpine (MK-801) have theoretical advantage over competitive agents such as GCS19755 in that competitive antagonist may be overcome by the pathologically high concentration of glutamate associated with cerebral ischemia but clinical trials using MK-801 were terminated because of toxic side effects and the induction of mitochondrial vacuolization.


Phase III trials in patients with acute stroke and trauma brain injury(TBI) using aptiganel(Cerestat,CNS-1102) are currently in process, but there is indication induce severe halluccination with this agent.


The degree of physiological blockade of NMDA receptors by Mg ions may also be important and its administration has been reported to be protective against cerebral ischemia.


Ampa receptor antagonist may well be more effective for both global and focal ischemia and they appear not to have the same psychomimetic effect as the NMDA antagonist agents.


Reluzole a new compound that inhibits presynaptic release of glutamate has neuroprotective effects in rodent models.


The anti epileptic drug remacemide is the only NMDA receptor antagonist with proven neuroprotective efficacy,in patients undergoing coronary artery surgery the perioperative administration of remacemide signifivantly reduced post operative neuropsychologic deficits.


to be continued

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Brain Ischemia and Protection (PART 1)

INTRODUCTION :(1,4,5)


Cerebral perfusion pressure(CPP) is the driving force for substrate(O2,glucose) delivery to the brain is defined as mean arterial pressure(MAP) minus intracranial pressure (ICP) and MAP is diastolic pressure plus 1/3(systolic pressure minus diastolic pressure).


The main substance use for energy production in the brain is glucose and O2.


Cerebral blood flow(CBF) can be used to calculate 0xygen delivery to the brain.


A standard formula is used  DO2 =CaO2 xCBF which :


DO2 is delivered oxygen, CaO2 is arterial oxygen content.


CaO2 is dependent on Hb content and PaO2,normal CaO2 is 16-20ml O2/100ml arterial blood and normal CBF is 50ml/100 gmin.


Normal DO2 is (16 to 20 mlO2/100ml)x50ml/100g/min)=8 to 10 mlO2/100g/min.


Since normal O2 consumption (VO2) is 3,5 t0 5ml/100g/min therefore a safety factor of 1,5 to 2 DO2 to VO2.


Local area of the brain may have a different ratio DO2 to VO2 secondary to a pathologic CBF or on altered metabolic rate.


Brain ischemia symptoms are seen when CBF falls to about 20ml/100g/min or DO2=4ml O2/100G/minutes.


When DO2=3 ml/100g/min or CBF of 15ml/100g/min or CPP 30-40 mmHg EEG silence occurs and when CBF of 8 to 12 mmHg or DO2=2ml/100g/min, cellular ion leakage and eventual cell death.


Although the normal brain in normal activities,can tolerate large temporary increases in ICP,PaCo2,severe hypotensiion of MAP(30-60 mmHg)but even mild hypotension can cause permanent brain damage when it occurs in a state of
asphyxiation or brain injured patient.


Therefore systolic blood pressure should not be allowed to decrease below 90 mmHg and CPP should be maintained at minimum of 70 mmHg.


Strategies intended to protect the brain from ischemic hypoxic insults attempt to interrupt or attenuate these pathophysiologic process.


Avoidance of inadequate cerebral perfusion pressure,prevention of hypoxaemia and the surgical decompression if intracranial mass lesion are by far the most important and effective neuroprotective interventions.


BRAIN METABOLISM : (3,5)


The metabolic fuel required by CNS is provided almost exclusively by glycogenolysis of glycogen stored mainly in the liver and muscle.


Glucose oxydation occurs in three successive stages;glycolysis,the citric acid cycle,and the the electron transport chain.


If oxygen levels are adequate glycolysis convert glucose molecule(six carbon) into two three carbon pyruvate with a net gain of two molecules of ATP(adenosine triphosphate)for each molecule of glucose metabolized.


Pyruvate then enters the citric acid cycle which regard to energy production primary generates NADH from NAD(nicotine adenine dinuceotide).


The mitochondria use oxygen to couple the conversion of NADH back to NAD with the production of ATP from ADP(adenosine diphosphate) and inorganic phosphate.This process called oxydative phosphorylation forms three ATP molecules for each NADH converted and yields 38 ATP molecules for each glucose molecule metabolized. In reality however one molecule of glucose yields no more than 30-35 molecules of ATP.Because some of the glucose(1%-3%)is diverted into pentose phosphate pathway,some is used to sustain the small store of glycogen in the brain,and 5% to 8% is metabolized to lactate.


The pathway need oxygen if oxygen not present the mitochondria can neither make ATP nor regenerate NAD from NADH.


The metabolism of glucose need NAD as a cofactor and is blocked in its absence.Thus in the absence of oxygen,glycolysis proceeds by a modified pathway termed anaerobic glycolysis which generates only two molecules of ATP per molecule of glucose cannot satisfy even the most basic energy requirements of the brain.


CELLULAR PROCESS THAT REQUIRE ENERGY:(3)


The largest energy requirement in the brain is pumping ion across the cell membrane. Consentration of sodium,potasium,and calcium of a neuron are maintained against large electrochemicals gradient with respect to the outside of the cell.


When a neuron is not excited there is a slow leak of potassium out of the cells and of sodium and calcium into the cells.


Neuronal activity markedly increases the flow potassium,sodium and calcium for maintaining normal cellular ion consentration. Since ion pumping uses ATP
as an energy source, the ATP requirement of active neurons is greater than that for unexcited neurons.


If the energy production does not meet the demand of energy use in the brain the neuron first become unexcitable and then irreversible damage.


Neuron require energy to maintain their structure and internal function.


The cell's membranes,internal organelle and cytoplasma are made of carbohydrates,lipids and proteins that require energy for their synthesis.


Ion channels,enzymes and cell structural components are important protein molecules that are continuosly synthesized and degraded in normally function
ing neurons.Their metabolism also require energy.


Most cellular synthesis take place in the cell body and energy is needed for transport of components down the axon to nerve terminal.


Thus energy is needed to maintain the intergrity of the neuron even in absence of electrophysiologic activity. 


BRAIN ISCHEMIA :(1,2,5)


All of the body organ the brain is the most sensitive to ischemia.


When the blood supply to the brain is decreased below a critical level,ischemic damaged occurs.


Ischemic injury is characterized by decrease in O2 delivery and supply of glucose and other metabolites.


The mechanism leading to neuronal damage are likely calcium is central in the pathophysiology, because the primary defect in cells mortality injured by a transient period of ischemia is an inability to regulate calcium ion since calcium ion play an important role in normal membrane excitation and cellular process.


Normally exracellular concentrations are maintained at a higher cocentration than free cytosolic concentrations by an ionic ATP dependent pump hence failure of ATP energy metabolism will have a deterious effect on this homeostasis.


One of the earliest manifestation of cerebral ischemia is an abrupt reduction in the concentration of energy metabolites and eventually ATP.


When tissue ATP is depleted the NaK ATP ase ion pumps fail, leading to Na+ inlux and K+ efflux and membrane depolarization accompanied by excessive release of excitatory neurotransmitter (glutamate,aspartate) and activation of NMDA(N methyl D aspartate),AMPA(@ amino-3-hydroxy-5-methyl-4-isoxazol proprionate) and voltage dependent calcium and sodium channels with results uncontrol influx Ca2+,which leads to disruption of mitochondrial and cell membranes and the release of free fatty acid(FFA) including arachidonic acids. 


Since ATP is necessary to clear the calcium from cytosol then increased cytosolic calcium levels occurs.


Calcium activates many intracellular enzymes(lipid peroxidases,proteases and  phospholipases) result enzymatic breakdown of membranes with subsequent release FFA and oxygen free radicals.


In addition activation of caspases (interleukin converting enzyme like protein) translocase and endonucleases initiate progressive structural changes of biological membranes and nucleosomal DNA(DNA fragmentation,inhibition of DNA repair).


Together these events lead to membrane degeneration of vascular and cellular structures and consecutive necrotic or apoptosis(programed cell death).


to be continued

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