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
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
