Brain cell survival strategies and neurosurgical cases

Brain cell survival strategies and neurosurgical cases

1. BRAIN CELL SURVIVAL STRATEGIES AND NEUROSURGICAL CASES Presenter- Dr. Suresh Pradhan Moderator- Prof. UC Sharma

2. Outline Neuroprotection: Introduction Pathogenesis and Pathophysiology of Neuronal injury Neuroprotection Strategies: Non- Pharmacological Pharamacological

3. Neuroprotection defined as the “protection of neurons” refers to strategies that prevent, antagonize, interrupt or slow the biochemical and molecular events which have the potential to cause the injury and death of brain cells used to potentially protect the brain in a number of different cerebral conditions including disease conditions, traumatic brain injury, perioperative period or stroke

4. brain injury is an important adverse complication of anaesthesia and surgery has a variable clinical manifestation from postoperative cognitive decline, transient ischaemic attacks to cerebrovascular accidents (CVAs) incidences vary according to the type of surgery, with up to 80% being reported in cardiac surgery

5. although the injury mechanisms differ between neurosurgical and non-neurosurgical procedures, the common denominator is failure of glucose and oxygen supply this triggers the cascades of inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity that lead to neuronal death by apoptosis and necrosis

6. Pathogenesis and Pathophysiology of Neuronal injury deprivation of oxygen supply to the brain tissue leads to activation of the ischemic cascade with a series of molecular mechanisms depletion of ATP and consequent high levels of lactate and unbuffered hydrogen ions hydrogen ions facilitate the generation of ferrous iron-mediated free radicals that result in astrocytes and glial cells injury

7. failure of energy dependent mechanisms including ion pumps leads to deterioration of membrane ion gradients, opening of selective and unselective ion channels, and equilibration of most intracellular and extracellular ions thus, potassium ions leave the cell, sodium, chlorine and calcium enter and many excitatory neurotransmitters (glutamate, aspartate) are released in potentially toxic concentrations

8. raised intracellular calcium accelerates many potentially injurious processes calcium activates phospholipases which hydrolyse membrane-bound glycerophospholipids to free fatty acids and these in turn facilitate free radical peroxidation of other membrane bound lipids calcium similarly activates both proteases that lyse structural proteins as well as nitric oxide synthase that initiates free radical mechanism

9. intracellular entry of calcium is made largely possible by the activation of two types of receptors: Voltage gated (L-type) and/or several N-methyl-d-aspartate (NMDA) and quisqualate (Q) post synaptic receptor/channel complexes by glutamate

10. neurons are particularly susceptible to ischaemic injury because they have a higher demand for energy and limited energy stores depletion of intrinsic central nervous system energy stores occurs within 2 to 4 minutes of anoxia

11. cellular energy failure threatens cell survival in 3 ways: in the absence of adequate energy stores, anaerobic glycolysis is stimulated, leading to lactic acidosis energy failure disrupts ion homeostasis: cellular influx of sodium & chloride with osmotically obligated water and the influx of calcium occur breakdown of cell structure occurs and is due both to a loss of ATP and to a rise in calcium concentration

12. i mportant strategies in neuroprotection include maintenance of: normoxia adequate cerebral perfusion pressure mild hypothermia timely surgical intervention other methods to reduce increasing intracranial pressure (such as mannitol) several methods of pharmacological neuroprotection

13. Neuroprotection Strategies Non- Pharmacological Pharamacological

14. Non- Pharmacological Methods they are simple, have a high risk‑benefit ratio and are relatively inexpensive include the following: Hypothermia Maintenance of CPP Induced arterial hypertension Blood glucose concentration Haemoglobin concentration Arterial CO 2 tension Brain tissue oxygen tension Osmotherapy Reducing embolic load

15. Hypothermia reduces brain damage from ischemia by preventing disruption of the brain-blood barrier lowers the basal metabolic rate and counteracts the ischemic cascade cerebroprotective effects of hypothermia have been utilized in two ways: Deep hypothermic circulatory arrest (DHCA) (20 o C) moderate hypothermia (32 o C)

16. Deep hypothermic circulatory arrest (DHCA) DHCA is used to facilitate surgery in complex congenital cardiac malformations, aortic arch replacement and giant intracerebral aneurysms of the posterior circulation DHCA is currently standard practice for aortic arch repair the most important problem with this technique is the limited time allowable for circulatory arrest before cerebral ischaemic damage arises

17. the safe period for DHCA is generally considered to be 60 minutes or less Svensson & colleagues reported that a cerebral ischaemic time exceeding 45 minutes was associated with a high risk of stroke barbiturates or etomidate or propofol have been used before DHCA to convey additional cerebral protection

18. many anaesthesiologists choose to administer barbiturates because they may offer additional neuroprotection beyond that provided by hypothermia alone it appears that the cerebral protective properties of barbiturate anaesthesia & hypothermia are additive, increasing the tolerance of the cerebral tissues to temporary global ischaemia

19. cooling is an imperfect process & barbiturates may provide a safety net in the case of focal incomplete cooling a second and perhaps more compelling reason for administering barbiturates before DHCA is the probability that they provide neuroprotection against air emboli during the rewarming period

20. moderate hypothermia has been found, in vitro as well as in vivo , to have cerebral protective effects, which is briefly summed up below: reduces metabolic demand of neurons cerebral vasoconstriction and, thereby, decrease in cerebral blood volume, brain oedema and intracranial pressure delayed anoxic/ischaemic depolarization

21. decreases excitatory neurotransmission prevention or amelioration of damaging biochemical derangements secondary to ischaemia depresses programmed cell death apoptotic cascade inhibits the inflammatory pathway, which leads to delayed cell death

22. Maintainence of CPP during neurosurgical operations, the brain is vulnerable to both global as well as focal ischaemic insults and it is absolutely imperative that adequate CPP be maintained in healthy adults with intact cerebral autoregulation, cerebral blood flow is maintained in a MAP range of 50‑150 mmHg this can be impaired in patients with underlying neurological disease as well as during certain neurosurgical operations

23. moderate and severe hypotension is treated vigorously and MAP be kept above 80 mmHg and CPP be kept above 70 mmHg this can be done with adequate fluids, vasopressors and decreasing the depth of anaesthesia

24. Induced arterial hypertension induced hypertension, done by raising the MAP 20‑ 40% above the pre‑operative levels, could increase CBF through the leptomeningeal circulation and prevent cerebral ischaemia , as the circle of Willis may be incomplete in 21% of patients

25. Indications of induced arterial hypertension in neurosurgery: endovascular procedures for aneurysm, carotid angioplasty and intra‑arterial thrombolysis traumatic brain injury with intracranial hypertension for surgical procedures extracranial to intracranial bypass surgery

26. Blood glucose concentration there is a general consensus that hyperglycaemia in patients at risk of cerebral ischaemia , either general or focal, increases the likelihood of brain injury and is associated with a worse neurological outcome a review of patients with a variety of neurosurgical disorders undergoing interventional neuroradiology also found that high blood glucose levels were associated with unfavourable neurological outcomes

27. hyperglycaemia appears to increase recruitment of ischaemic penumbral neurons into the infarcted area, but it had little impact on irreversibly ischaemic neurons at present, there is no consensus or data on the optimal intra‑operative blood glucose level that would not compromise neurological integrity the aim of the anaesthesiologist would be to prevent extremes of blood sugar fluctuations and maintain blood glucose level between 140 and 180 mg/dl

28. Haemoglobin concentration potential mechanisms for anaemia ‑induced brain injury can be attributed to: tissue hypoxia inflammation reactive oxygen species generation excitotoxicity activation of deleterious hypoxic cell signaling pathways

29. the precise haemoglobin threshold for brain tissue injury during neurologic procedures leading to poor outcomes is not known however, on the basis of the available evidence, it is recommended that in neurosurgical patients, pre‑operative and intra‑operative haemoglobin levels should be maintained at least 12 and 9 g/dl, respectively

30. other non‑pharmacological measures to prevent cerebral ischaemia , particularly in neurosurgical patients, would be: to maintain adequate cerebral blood flow by avoiding hypocarbia provide brain relaxation by administering osmotic diuretics especially in the presence of intracranial hypertension

31. Pharmacological Neuroprotection pharmacological neuroprotection includes both anaesthetic and non‑ anaesthetic drugs both of which have been extensively studied in the laboratory based on sound experimental evidence, many neuroprotective drugs have been developed, but clinical trials of most drugs in man have been disappointing till date, there are no drugs, either anaesthetic or non‑ anaesthetic , with proven neuroprotective efficacy that can decrease brain injury in the peri‑operative period

32. Mechanism of Neuroprotection by Pharmacological Agents Prevention of Early Ischemic Injury Prevention of Reperfusion Injury

33. returning blood contains leukocytes that may occlude small vessels and release toxic products neuroprotective agents that work primarily during reperfusion may have a longer window of therapeutic effect than drugs that work earlier in the ischemic cascade

34. Prevention of Early Ischemic Injury neuroprotective agents limit acute injury to neurons in ischemic penumbra neurons in the penumbra are less likely to suffer irreversible injury at early time points than are neurons in the infarct core many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury

35. Prevention of Reperfusion Injury neuroprotective agents prevent potentially detrimental events associated with return of blood flow although return of blood flow to the brain is generally associated with improved outcome, reperfusion may contribute to additional brain injury

36. Targets for Neuroprotection Inflammation Oxidative Stress Blood-Brain Barrier Disruption Excitotoxicity Apoptosis Autophagy

37. Anaesthetic Neuroprotection Intravenous anaesthetic agents Barbiturates : of the clinically available anaesthetics , barbiturates have the greatest potential to protect the brain from ischaemic injury barbiturate associated protection is mediated via reduced metabolic demand deep barbiturate anaesthesia can reduce CMR to the same extent as hypothermia to 30 o C

38. other potential beneficial effects of barbiturates are: reduction of elevated intracranial hypertension producing favorable redistribution of blood towards ischaemic tissue by constricting the vessels in the non-ischaemic cortex suppression of abnormal or seizure-like activity also been suggested that barbiturates exert neuroprotective effects through anti-oxidant or free radical scavenging actions

39. Etomidate : like barbiturates, etomidate produces EEG burst suppression and reduces CMR for glucose and oxygen clinically, etomidate decreases CBF, CMRO2 and ICP whereas carbon-dioxide reactivity, haemodynamic stability and cerebral perfusion pressure (CPP) are maintained

40. it inhibits release of excitatory neurotransmitters it may be useful for neuroprotection when temporary vessel occlusion is required it is routinely used in some centers to increase safety during temporary arterial occlusion employed for surgery of complex cerebral aneurysms has a low incidence of hemodynamic instability at doses sufficient to depress the EEG: a major advantage over thiopental

41. etomidate has been associated with significant adrenocortical suppression, even when administered as a single injection this effect of the drug has greatly limited its utility in usual anaesthetic care but not its utility in neurosurgical cases in which patients are routinely administered high doses of steroids EEG excitation, abnormal movements & vomiting are other adverse effects etomidate has been associated with renal failure presumed secondary to the propylene glycol vehicle

42. Propofol : metabolic changes resulting from propofol anaesthesia closely resemble the homogenous depression of CMR caused by barbiturates and etomidate propofol reduces cerebral metabolism with a consensual reduction in EEG activity, O2 consumption & cerebral blood flow propofol also reduces voltage-activated sodium channel conductance at concentrations within the clinical range Its antioxidant properties may also be of benefit

43. high doses may produce hypotension, which reverses rapidly upon discontinuation (usually within 5-10 minutes) administration of propofol to head injured patients with elevated ICP has been associated with a reduction in ICP but also of CPP propofol infusion titrated to produce unresponsiveness (8 mgkg-1hr-1) in humans, resulted in 55% depression in CMR for glucose, as measured using positron emission tomography

44. Ketamine : anesthetists have long assumed that ketamine’s role in neuroanesthesia is limited because of its association with increased intracranial pressure there are now evidences that when ketamine is used as an adjuvant anesthetic agent along with mechanical ventilation to maintain normocapnia, ketamine does not have adverse cerebral hemodynamic effects furthermore, ketamine possesses a unique pharmacologic profile that provides analgesia, bronchodilation, and sympathetic stimulation, thereby reducing patients’ vasoactive agent requirements

45. following ischaemia , the pathological mechanism which results in cerebral infarction involves the release of a number of neurotransmitters a major one being Nmethyl -D-aspartate (NMDA) ketamine is a noncompetitive antagonist at NMDA receptors & may therefore offer protection from the adverse effects of cerebral ischaemia

46. caution must be exercised because of ketamine’s action at the N-methyl-d-aspartate receptor (NMDAR), as ketamine may antagonize both neuroprotective and neurodestructive NMDAR mediated pathways still, ketamine may prove to be a safe part of a neuroanesthetic regimen, and it should no longer be considered absolutely contraindicated as a result of its cerebral hemodynamic effects

47. B) Inhalational agents: Isoflurane : offers a similar level of metabolic depression as barbiturates at a concentration less likely (than barbiturates) to be accompanied by severe cardiovascular depression or prolonged recovery can suppress brain electrical activity to the point of isoelectricity at clinically useful concentrations (<2MAC)

48. is a potent inhibitor of CMR and CMRO2 in all species studied in addition to its GABAergic effects, isoflurane has also been shown to inhibit multiple voltage-gated calcium currents in hippocampal pyramidal neurons has been shown to significantly inhibit glutamate receptor activation and ischaemia induced calcium influx

49. the majorities of human studies indicate that isoflurane below 1 % has little effect on ICP isoflurane at inspired concentrations of 0.6 to 1.1 MAC does not alter CBF although 1.6 MAC doubles CBF

50. Sevoflurane : as with isoflurane and barbiturates, sevoflurane produces a dose-dependent decrease in CMR autoregulation appears to be well maintained in patients with cerebrovascular disease undergoing sevoflurane anaesthesia in animal models, sevoflurane not only reduced brain damage following focal ischaemia but also improved neurological outcome following incomplete global ischaemia

51. Desflurane : although thiopental treatment for brain protection is effective in decreasing ischaemic injury, the doses required for EEG suppression prolong recovery times inhalation anaesthetics such as desflurane can also produce EEG silence but allow a more rapid recovery at the end of surgery

52. desflurane treatment for cerebral protection significantly increases brain tissue oxygenation & pH above control levels attenuates hypoxic changes during brain artery occlusion also attenuates ischaemic lactic acidosis & decreases in pH during brain artery occlusion

53. Nitrous oxide : some forms of cerebral protection may be adversely affected by the presence of nitrous oxide in general, barbiturates have limited efficacy as cerebral protectants in animal studies that employed nitrous oxide as part of the anaesthetic management however, barbiturates were efficacious in those studies that did not employ nitrous oxide as part of the anaesthetic management it decreases isoflurane’s efficacy as a neuroprotectant when used during incomplete cerebral ischaemia

54. Non-anesthetic agents as Neuroprotectants Glucocorticosterids Tirilazad mesylate (TM) Superoxide dismutase (SOD) Nimodipine Nicardipine Lidocaine Furosemide

55. Mannitol Papaverine Insulin Tromethamine Perfluorocarbons Other drugs

56. Glucocorticosterids : their efficiency in reducing vasogenic peritumoral edema is well documented the Second National Acute Spinal Cord Injury Study (NASCIS II) demonstrated that high dose methylprednisolone (30 mgkg-1 bolus followed by 5.4 mgkg-1 for 23 hours) was of benefit in spinal cord injury if treatment was instituted within 8 hours of injury

57. at these doses, methylprednisolone inhibits lipid peroxidation of neuronal, glial, and vascular membranes caused by O2 free radicals lipid peroxidation is a process implicated in the pathophysiology of secondary central nervous system (CNS) injury however, lower doses had proven ineffective in the NASCIS I study

58. it has been demonstrated that similar high doses of methylprednisolone were of benefit in humans with severe head injury the major mechanism for the neuroprotective effect of corticosteroids is probably inhibition of lipid peroxidation this effect is extremely dose-dependent, which can account for methylprednisolone’ effect at high doses (30mgkg-1) but not low dose

59. methylprednisolone’s possible efficacy in subarachnoid haemorrhage induced vasospasm has also been ascribed to inhibition of lipid peroxidation the antiedema effect of methylprednisolone may at least in part be a result of other actions that are not so dependent on high dose administration gastrointestinal bleeding and infection are two complications attributed to corticosteroids use

60. glucocorticosteroids such as dexamethasone and methylprednisolone cause or exacerbate hyperglycemia hyperglycemia has been shown to increase brain injury in ischaemia when corticosteroids are used it is essential to maintain precise control of blood glucose levels the use of glucocorticoids is not recommended for improving outcome or reducing ICP in patients with severe head injury

61. Tirilazad mesylate (TM) is a 21-aminosterid ( lazaroid ) that was developed specifically to maximize the inhibition of lipid peroxidation by glucocorticoids such as methylprednisolone, but eliminate the unwanted glucocorticoids effects the lazaroids are potent antioxidants, 100 times more potent than the corticosteroids, & therefore may be efficacious in the clinical management of acute CNS injury

62. mechanism of action appears to be cell membrane preservation by inhibition of lipid peroxidation brain levels of the antioxidants vitamin E and, to a lesser extent, vitamin C are preserved in ischaemia -reperfusion, when TM is used post ischaemic recovery of extracellular calcium is more rapid with TM use, as is the recovery of intracellular pH and somatosensory evoked potentials

63. in subarachnoid haemorrhage , a large phase II trial showed an improvement in outcome with 6 mgkg -1 day -1 (given in divided doses, 6 hourly) tirilazad administered for 10 days the effect was most marked in men in whom mortality was reduced from 20% to 6% multicentre studies of high dose (15 mgkg -1 day -1 ) tirilazad in women have shown a significant reduction in the incidence of vasospasm associated with aneurysmal subarachnoid haemorrhage and the mortality in patients who were neurological grade IV or V on admission

64. there is also increasing interest in using tirilazad in combination with thrombolytic agents in the management of ischaemic strokes

65. Superoxide dismutase (SOD) is a specific scavenger of superoxide anion superoxide anion is capable of producing significant biological injury it is generated on reperfusion of post ischaemic tissues because, superoxide dismutase (SOD) has a biological half-life of only 5 minutes, it has been conjugated with polyethylene glycol (PEG-SOD) for use in humans

66. in a trial of PEG-SOD in patients with severe head injury, treatment was a single bolus IV administration, with a mean time from injury to treatment of approximately 4 hours the % of time the ICP was above 20mmHg & the amount of mannitol required to control ICP were less in the moderate dose PEG-SOD (5000 Ukg-1) & high-dose PEG-SOD (10000 Ukg-1) treated patients than in controls furthermore, outcome at 6 months was better in the highdose PEG-SOD treated patients (i.e., fewer vegetative or dead)

67. Nimodipine antagonizes the entry of calcium into cells by acting on dihydropyridine receptors in turn ameliorates the lactic acidosis, which occurs during ischaemia increases CBF, particularly in regions of moderate ischaemia may be particularly effective at neuroprotection during hyperventilation, which is a common intervention during brain surgery alkalosis is particularly detrimental to neuronal survival during ischaemia

68. nimodipine is particularly effective in focal cerebral ischaemia , & thus would be expected to offer protection for intraoperative focal ischaemia such as temporary vessel occlusion and brain retraction in light of nimodipine’s safety as well as its efficacy when given prior to injury, it appears reasonable to consider nimodipine for intraoperative use, particularly where focal ischaemia can be anticipated (e.g., brain retraction or temporary vessel occlusion)

69. has a beneficial effect on neurological outcome in patients recovering from aneurysmal subarachnoid haemorrhage and has become a standard prophylactic therapy in such patients in these patients, use of nimodipine result in a lower incidence of delayed ischaemic deficits or death this effect is thought to be mediated by nimodipine’s effect on small vessel cerebral vasospasm

70. treatment with Nimodipine decreases BP, decreases systemic vascular resistance & increases cardiac output neurological outcome was found to be better in patients treated with nimodipine within 24 hours of the onset of ischaemic stroke

71. Nicardipine is a calcium antagonist cerebral ischaemia causes a rapid shift of calcium from the extracellular spaces into cells directly reduces calcium entry into ischaemic cells nicardipine has been administered into venous reservoir before DHCA

72. Lidocaine neuropsychologic deficits remain vexing complications after both coronary artery & valve operations studying patients undergoing aortic or mitral valve operation, Mitchell & colleagues found that a relatively simple & low-risk intervention, prophylactic infusion of lidocaine, substantially improved neuropsychologic outcome at 10 days, 10 weeks, and 6 months compared to a placebo control

73. possible mechanisms for cerebral protection by lidocaine include: deceleration of ischaemic transmembrane ion shifts reduction in CMR modulation of leukocyte activity reduction of ischaemic excitotoxin release

74. Furosemide it is a sulfonamide that inhibits distal tubular reabsorption it has been shown to decrease ICP effectively without the transient ICP increase that can be seen with mannitol an additional action of furosemide, which may be of benefit, is its reduction of cerebrospinal fluid formation the dose of furosemide may be upto 1 mgkg-1, depending on the degree of diuresis required

75. Mannitol is widely used in neurosurgical operations involving patients with cerebral edema &/or mass effect some of mannitol’s potentially beneficial effects include: osmotic diuresis increased blood viscosity free radical scavenging is used for control of raised intracranial pressure (ICP) after brain injury

76. may also be used when high ICP is demonstrated in the intensive care unit it should be given as a bolus intravenous infusion, over 10 to 30 minutes, in doses ranging from 0.25 to 1g kg -1 it is more effective and safer when administered in bolus infusion doses than as a continuous infusion

77. in patients receiving mannitol, hypovolemia should be avoided, serum osmolarity should be kept below 320 mOsm & serum sodium should be kept below 150 mEqL -1 mannitol has been added to the venous reservoir before DHCA is employed is well known to reduce cerebral edema after ischaemia can also scavenge free radicals & thus reduce tissue damage caused by superoxide radicals

78. Papaverine is a smooth muscle relaxant & may work by blocking calcium channels it is used for topical application on arteries to reverse vasoconstriction resulting from manipulation (mechanical ‘vasospasm’) it has also been given as intra-arterial injection

79. however, there is one case report of transient severe brain stem depression during intraarterial papaverine infusion for cerebral vasospasm usual concentration used is 30mg in 9cc saline it is applied on to vessels with gelfoam or cotton pledget soaked in this mixture & left in contact with vessels for 2 minutes

80. the solution can directly be applied to the vessels with a syringe & left in contact with them local application of controlled-release papaverine drug pellets have been safely used in preventing vasospasm during cerebral aneurysm surgery, drug pellets were placed in cisterns over arterial segments

81. Insulin Elevated intracellular glucose concentration at the time of a cerebral ischaemic insult may result in increased cellular lactic acidosis, & this worsens ischaemic injury insulin has been shown to have a neuroprotective effect (Strong et al. 1990) and some observations in human are in keeping with these experimental findings (Plum 1983 and Lam et al. 1991)

82. Tromethamine tromethamine (THAM), a weak base which crosses the plasma membrane and acts directly on intracellular acidosis has been used with success in models of experimental head injury THAM has been used in head injuries in human with favorable effects on brain edema and intracranial pressure (Wolf et al. 1993)

83. Perfluorocarbons use of perfluorocarbons is a novel approach to decreasing cerebral emboli associated with cardiac surgery these compounds have high gas affinity & so may decrease cerebral gaseous microemboli they may improve flow characteristics in areas of decreased perfusion

84. Other drugs Levy & collegues have reported a trend toward decreased incidence of stroke in patients receiving high dose aprotinin the mechanism of action is unknown however the anti-inflammatory properties of aprotinin may be thought to be responsible

85. a trial designed to determine the myocardial effects of acadesine , an adenosine-regulating agent, demonstrated lower incidence of stroke in patients receiving the drug the possible mechanism of action is unknown, but may involve decreased excitatory transmitter release or reduced granulocyte accumulation

86. Chemical brain retractor concept this concept includes the use of a total IV anaesthesia technique, mild hypocapnia & mannitol with strict monitoring & maintenance of the global cerebral homeostasis this contributes to decrease brain volume & ICP it allows the best possible access to the operation site, while avoiding excessive pressures under the surgical brain retractors