Textbook of Neuroanaesthesia and Critical Care - part 2 ppsx

for oxygen, intracranial pressure and the electroencephalogram are similar to those of isoflurane in the rabbit. Anesthesiology 1988; 68: 548 – 551. 72. Lutz LJ, Milde JH, Milde LN. The cerebral functional, metabolic, and hemodynamic effects of desflurane in dogs. Anesthesiology 1990; 73: 125 – 131. 73. Muzzi DA, Losasso TJ, Dietz NM, Faust RJ, Cucchiara RF, Milde LN. The effect of desflurane and isoflurane on cerebrospinal fluid pressure in humans with supratentorial mass lesions. Anesthesiology 1992; 76: 720 – 724. 74. Rampil IJ, Lockhart SH, Eger El, Weiskopf RB. Human EEG dose response to desflurane. Anesthesiology 1990; 73: A1218. 75. Tonner PH, Scholz J, Krause T, Paris A, Von Knobelsdroff G, Schulte an Esch J. Administration of sufentanil and nitrous oxide blunts cardiovascular responses to desflurane but does not prevent an increase in middle cerebral artery flow velocity. Eur J Anaesthesiol 1997; 14: 389 – 396. 76. Bundgaard H, Von Oettingen G, Larsen KM et al. Effects of sevoflurane on intracranial pressure, cerebral blood flow and cerebral metabolism. A dose-response Pa g e 32 study in patients subjected to craniotomy for cerebral tumours. Acta Anaesthesiol Scand 1998; 42: 621 – 627. 77. Summors A, Gupta A, Matta BF. Dynamic cerebral autoregulation during sevoflurane anaesthesia: a comparison with isoflurane. Anesth Analg 1999; 88: 341 – 345. 78. Gupta S, Heath K, Matta BF. The effect of incremental doses of sevoflurane on cerebral pressure autoregulation in humans: a transcranial Doppler study. Br J Anaesth 1997; 79: 469 – 472. 79. Matta BF, Mayberg TS, Lam AM. Direct cerebrovasodilatory effects of halothane, isoflurane and desflurane during propofol- induced isoelectric encephalogram in humans. Anesthesiology 1995; 83: 980 – 985. 80. Heath K, Gupta S, Matta BF. Direct cerebral vasodilatory effect of sevoflurane. Anesthesiology 1997; 87: A177. 81. Heath KJ, Gupta S, Matta BF. The effects of sevoflurane on cerebral hemodynamics during propofol anesthesia. Anesth Analg 1997; 85: 1284 – 1287. 82. Gupta S, Heath K, Matta BF. Effect of incremental doses of sevoflurane on cerebral pressure autoregulation in humans. Br J Anaesth 1997; 79: 469 – 472. 83. Kassel NF, Hitchon PW, Gerk MK, Sokoll MD, Hill TR. Alterations in cerebral blood flow, oxygen metabolism, and electrical activity produced by high dose sodium thiopental. Neurosurgery 1980; 7: 598 – 603. 84. Milde LN, Milde JH, Michenfelder JD. Cerebral functional, metabolic, and hemodynamic effects of etomidate in dogs. Anesthesiology 1985; 63: 371 – 377. 85. Ramani R, Todd MM, Warner DS. The cerebrovascular, metabolic and electroencephalographic effects of propofol in the rabbit – a dose response study. J Neurosurg Anesthesiol 1992; 4: 110 – 119. 86. Van Hemelrijck J, Van Aken H, Plets C, Goffin J, Vermaut G. The effects of propofol on intracranial pressure and cerebral p erfusion pressure in patients with brain umours. Acta Anaesthesiol Belg 1989; 40: 95 – 100. 87. WeeksJ, Todd MM, Warner DS, Katz J. The influence of halothane, isoflurane, and pentobarbital on cerebral plasma volume in hypocapnic and normocapnic rats. Anesthesiology 1990; 73: 461 – 466. 88. Fox J, Gelb AW, Enns J, Murkin JM, Farrar JK, Manninen PH. The responsiveness of cerebral blood flow to changes in arterial carbon dioxide is maintained during propofol-nitrous oxide anesthesia in humans. Anesthesiology 1992; 77: 453 – 456. 89. Carlsson C, Smith DS, Keykhah MM, Englebach I, Harp JR. The effects of high dose fentanyl on cerebral circulation and metabolism in rats. Anesthesiology 1982; 57: 375 – 380. 90. Keykhah MM, Smith DS, Carlsson C, Safo Y, Englebach I, Harp JR. Influence of sufentanil on cerebral metabolism and circulation in the rat. Anesthesiology 1985; 63: 274 – 280. 91. McPherson RW, Krempasanka E, Eimerl D, Traystman RJ. Effects of alfentanil on cerebral vascular reactivity in dogs. Br J Anaesth 1985; 57: 1232 – 1238. 92. Murkin JM, Ferrar JK, Tweed WA, McKenzie FN, Guiraudon G. Cerebral autoregulation and flow/metabolism coupling during cardiopulmonary bypass: the influence of PaCO 2 . Anesth Analg 1987; 66: 825–832. 93. Sperry RJ, Bailey PL, Reichman MV, Peterson PB, Pace NL. Fentanyl and sufentanil increase intracranial pressure in head trauma patients. Anesthesiology 1992; 77: 416 – 420. 94. Åkeson J, Björkman S, Messeter K, Rosén I, Helfer M. Cerebral pharmacodynamics of anaesthetic and subanaesthetic doses of ketamine in the normoventilated pig. Acta Anaesthesiol Scand 1993; 37: 211 – 218. 95. Menon DK, Burdett NG, Carpenter TA, Hall LD. Functional MRI of ketamine-induced changes in rCBF: an effect at the NMDA receptor? (abstract). Br J Anaesth 1993, 71: 767P. 96. Mayberg TS, Lam AM, Matta BF, Domino K, Winn HR. Ketamine does not increase cerebral blood flow velocity or intracranial p ressure during isoflurane-nitrous oxide anesthesia in patients undergoing craniotomy. Anesth Analg 1995; 81: 84 – 89. 97. Forster A, Juge O, Morel D. Effects of midazolam on cerebral blood flow in human volunteers. Anesthesiology 1982; 56: 453– 455. 98. Fleischer JE, Milde JH, Moyer TP, Michenfelder JD. Cerebral effects of high-dose midazolam and subsequent reversal with RO 15 – 1788 in dogs. Anesthesiology 1988; 68: 234 – 242. 99. Zornow MH, Fleischer JE, Scheller MS et al. Dexmedetomidine, an alpha 2-adrenergic agonist, decreases cerebral blood flow in the isoflurane anaesthetised dog. Anesth Analg 1990; 70: 624 – 630. 100. McPherson RW, Koehler RC, Kirsch JR, Traystman RJ. Intraventricular demedetomidine decreases cerebral blood flow during normoxia and hypoxia in dogs. Anesth Analg 1997; 84: 139 – 147. 101. Ducey JP, Deppe AS, Foley FT. A comparison of the effects of suxamethonium, atracurium and vecuronium on intracranial haemodynamics in swine. Anaesth Intens Care 1989; 17: 448 – 455. 102. Kovarik WD, Lam AM, Slee TA, Mathisen TL. The effect of succinylcholine on intracranial pressure, cerebral blood flow velocity and electroencephalogram in patients with neurologic disorders (abstract). Anesthesiology 1991; 75: 207. 103. Stirt JA, Grosslight KR, Bedford RF, Vollmer D. 'Defasciculation' with metocurine prevents succinylcholine-induced increases intracranial pressure. Anesthesiology 1987; 67: 50 – 53. 104. Siesjo B.K. Pathophysiology and treatment of focal cerebral ischaemia. Part I: pathophysiology. J Neurosurg 1992; 77: 169– 184. 105. Robertson CS, Contant CF, Gokaslan ZL, Narayan RK, Grossman RG. Cerebral blood flow, arteriovenous Pa g e 33 oxygen difference, and outcome in head injured patients. J Neurol Neurosurg Psychiatry 1992; 55: 594 – 603. 106. Bouma GJ, Muizelaar JP, Stringer WA, Choi SC, Fatouros P, Young HF. Ultra early evaluation of regional cerebral blood flow in severely hea d -injured patients using xenon-enhanced computerized tomography. J Neurosurg 1992; 77: 360 – 369. 107. Martin NA, Patwardhan RV, Alexander MJ et al. Characterization of cerebral hemodynamic phases following severe head trauma: hypoperfusion, hyperaemia and vasospasm. J Neurosurg 1997; 87: 9 – 19. 108. Martin NA, Doberstein C, Zane C, Caron MJ, Thomas K, Becker DP. Posttraumatic cerebral arterial spasm: transcranial Doppler ultrasound, cerebral blood flow and angiographic findings. J Neurosurg 1992; 77: 575 – 583. 109. Marion DW, Darby J, Yonas H. Acute regional cerebral blood flow changes caused by severe head injuries. J Neurosurg 1991; 74: 407 – 414. 110. McLaughlin MR, Marion DW. Cerebral blood flow within and around cerebral contusions. J Neurosurg 1996; 85: 871 – 876. 111. Menon DK, Minhas P, Herrod NJ et al. Cerebral ischaemia associated with hyperventilation: a PET study. Anesthesiology 1997; 87: A176. 112. Chan KH, Dearden NM, Miller JD, Andrews PJ, Midgley S. Multimodality monitoring as a guide to treatment of intracranial hypertension after severe brain injury. Neurosurgery 1993; 32: 547 – 552. 113. Feldman Z, Kanter MJ, Robertson CS et al. Effect of head elevation on intracranial pressure, cerebral perfusion pressure and cerebral blood flow in head injured patients. J Neurosurg 1992; 76: 207 – 211. 114. Lassen NA, Agnoli A. The upper limit of autoregulation of cerebral blood flow on the pathogenesis of hypertensive encephalopathy. Scand J Clin Lab Invest 1973; 30: 113 – 116. 115. Voldby B, Enevoldsen EM, Jensen FT. Cerebrovascular reactivity in patients with ruptured intracranial aneurysm. J Neurosurg 1985; 62: 59 – 67. 116. Pickard JD, Matheson M, Patterson J, Wyper D. Prediction of late ischemic complications after cerebral aneurysm surgery by the intraoperative measurement of cerebral blood flow. J Neurosurg 1980; 53: 305 – 308. 117. Kassell NF, Peerless SJ, Durward QJ, Beck DW, Drake CG, Adams HP. Treatment of ischaemic deficits from vasospasm with intravascular volume expansion and induced arterial hypertension. Neurosurgery 1982; 11: 337 – 343. 118. Yamaura I, Tani E, Maeda Y, Minami N, Shindo H. Endothelin-1 of canine basilar artery in vasospasm. J Neurosurg 1992; 76: 99 – 105. 119. Clozel M, Watanabe H. BQ-123, a peptidic endothelin ETA receptor antagonist, prevents the early cerebral vasospasm following subarachnoid hemorrhage after intracisternal but not intravenous injection. Life Sci 1993; 52: 825 – 834. 120. Jakobsen M, Skj3/4dt T, Enevoldsen E. Cerebral blood flow and metabolism following subarachnoid hemorrhage: effect of subarachnoid blood. Acta Neurol Scand 1991; 8: 226 – 233. 121. Pickard JD, Murray GD, Illingworth R et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid hemorrhage: British Aneurysm Nimodipine Trial. BMJ 1989; 298: 636 – 642. 122. Origitano TC, Wascher TM, Reichman OH, Anderson DE. Sustained increased cerebral blood flow with prophylactic hypervolemic haemodilution ('Triple – H' Therapy) after subarachnoid haemorrhage. Neurosurgery 1990; 27: 729 – 738. 123. Darby JM, Yonas H, Marks EC, Durham S, Snyder RW, Nemoto EM. Acute cerebral blood flow response to dopamine-induced hypertension after subarachnoid hemorrhage. J Neurosurg 1994; 80: 857 – 864. 124. Zakhary R, Gaine SP, Dinennan JL et al. Heme oxygenase 2: endothelial and neuronal localisation and role in endothelial- dependent relaxation. Proc Natl Acad Sci USA 1996; 93: 795 – 798. 125. Iadecola C. Neurogenic control of the cerebral microcirculation: is dopamine mining the store? Nature Neurosci 1998; 1: 363– 364. Pa g e 35 3— Mechanisms of In j ur y and Cerebral Protection Patrick W. Doyle & Arun K. Gupta Mechanisms of Injury 37 Cerebral Protection 41 Clinical Practice 45 References 45 Pa g e 37 Mechanisms of neural injury, cerebral protection and cerebral resuscitation have been an area of intensive research over the last 20 years and the pathophysiological and biochemical processes responsible for the development and propagation of neural injury are becoming clearer. Despite this explosion of research, current approaches to reducing permanent injury have remained largely unchanged over the past few decades. The pathophysiological processes that lead to neuronal cell death and loss of function are similar whether the CNS insult is the consequence of intraoperative injury, stroke or trauma. In its correct terminology, cerebral protection refers to interventions aimed at reducing neural injury that are instituted before a possible ischaemic event, while cerebral resuscitation refers to interventions that occur after such an event. 1 In practice, many of the mechanisms involved in both phases of the process are identical and the following discussion will deal with both forms of intervention as one. Mechanisms of In j ur y All brain injury can be thought of as being constituted of basic primary, secondary and molecular and biochemical processes. Whatever the primary insult, there will always be secondary and molecular damage, not only in the core of the lesion but also in the penumbral region. Central to all mechanisms of injury are cerebral ischaemia and hypoxia. Global ischaemia refers to events which result in complete hypoperfusion of the entire organ or where no potential for recruitment of collateral flow exists. Focal ischaemia refers to the occlusion of an artery distal to the circle of Willis, which permits some collateral flow, thus resulting in a dense ischaemic core with a partially perfused surrounding penumbral zone. 1 Tissues in the penumbral zone may be more salvageable and hence provide a realistic target for neuroprotection. B asic Mechanisms of Injury All the principal types of brain damage that occur clinically can now be reproduced in experimental models. 2,3 These can be classified as traumatic, ischaemic or hypoxic. Traumatic brain injury may be due to the trauma associated with accidents or personal violence. Alternatively, the trauma may be iatrogenic and accompany a variety of operative procedures, including retraction, shear forces, direct tissue destruction, haemorrhage and vessel disruption with subsequent infarction. These injuries are typically followed b y brain swelling, leading to an increase in intracranial volume and intracranial pressure and a consequent reduction in cerebral blood flow. In addition to direct tissue injury, acceleration-deceleration forces may result in shearing of nerve fibres and microvascular structures in the process termed diffuse axonal injury. 4,5 While this was originally thought to occur at the time of injury, there is accumulating evidence that the event of axonal shearing is the culmination of processes that mature over hours. Secondary insults are initiated as a consequence of the primary injury but may not be apparent for an interval following the injury. Intracranial haemorrhage is the most common local structural cause of clinical deterioration and death in patients who have experienced a lucid interval after traumatic injury. 6,7,8 The pathophysiology associated with this process may reflect simple p hysiological consequences of ischaemia arising from pressure effects to underlying and distant brain regions, shift of vital structures and axonal disruption, reductions in cerebral blood flow and metabolism, hydrocephalus and herniation. However, metabolic processes may cause more subtle changes and ischaemia may not just be due to local microcirculatory compression but also the consequence of vasoactive substances released from the haematoma. In addition, glucose utilization has also been found to be markedly increased in pericontusional and perihaemorrhagic regions, possibly due to activation of excitatory neuronal systems. 2,9 In addition, extravasated subarachnoid blood can cause vasospasm both locally and at distant sites with aggravation of ischaemia. Systemic physiological insults may occur as a consequence of the primary lesion but can contribute to worsening neural injury. These include hypoxia, hypotension, hypercarbia, hyperthermia, anaemia and electrolyte disturbances. Hypoxia may be the result of airway obstruction, aspiration, thoracic injury, primary hypoventilation or pulmonary shunting. 3 Hypotension has been found to occur in 32– 35% of patients in emergency departments, which may be due to systemic causes. 7 This causes a decrease in cerebral perfusion pressure, which may be aggravated by a high ICP, disruption of cerebrovascular autoregulation, vasospasm and change in cerebral blood flow patterns. Hyperthermia may be due to infection, thrombophlebitis, drug reactions or a defect in the thermoregulatory system. This results in excessive excitotoxic neurotransmitter release, altered protein kinase C activity and augmented pathophysiological effects of ischaemia. Hypercarbia causes vasodilatation of cerebral blood vessels, with increased ICP, and exacerbation of any mass or oedema effect. It may also be associated with cerebral metabolic acidosis. Pa g e 39 injury. 19 While the general consensus is that preischaemic hyperglycaemia is deleterious, in some studies it has been shown to delay the onset of ischaemic Ca ++ influx from the ECF and potentiate reextrusion of Ca ++ following recirculation. These findings may reflect the modulatory effects of the type of ischaemia (focal versus global), its duration and extent and the completeness of the ischaemic insult. 10,20 It is thought that acidosis enhances production of reactive free radicals, causes oedema, aggravated tissue damage and delayed seizures and prevents recovery of mitochondrial metabolism. 14,19 However, it still remains to be fully established whether exaggerated intra-ischaemic acidosis enhances postischaemic production of reactive oxygen species (ROS). Ionic Pum p Failure A variety of membrane ionic pumps, including Na + K + , Na +– Ca ++ , and Ca ++ –H + , as well as Cl – and HCO 3 – leakage fluxes, maintain electrical and concentration gradients for various ions across the cell membrane and hence generate the resting membrane potential. 21 Since these are energy-consuming processes, ischaemia-induced decreases in ATP production result in loss of ionic pump function, with changes in transmembrane concentrations of ions and electrical fluxes. Na + and Cl – influxes result in cellular swelling and osmolytic damage, whilst increased cytosolic Ca ++ sets off a cascade of events that are discussed later in this chapter. K + also rapidly leaves cells. Not only must one consider ATP pump failure but in the 'milieu' of ischaemic tissue, local depolarization leads to activation of ionic conductances. The increased energy demands of de p olarization ma y tri gg er overt ener gy failure and conse q uentl y p rolon g transient ionic fluxes. 22 Siësjo and Siësjo describe three major cascades of reactions: 19 1. sustained perturbation of cell Ca ++ metabolism; 2. persistent depression of protein synthesis; 3. programmed cell death. Calcium Ca ions play an important role in normal membrane excitation and cellular processes. 21 Normally extracellular concentrations are maintained at a higher concentration than free cytosolic concentrations by an ionic ATP-dependent pump. Failure of ATP energy metabolism will have a deleterious effect on this homoeostasis. 23 It is postulated that the primary defect in cells mortally injured by a transient period of ischaemia is an inability to regulate Ca ++ . 24 The slow gradual rise in Ca ++ is caused by the release of glutamate from the presynaptic nerve endings, primarily via activation of receptors of the NMDA type. This leads to excessively high cytosolic Ca ++ levels. Activation of the AMPA receptors also results in a Na +– dependent depolarization which causes further Ca ++ influx via voltage-gated channels. The secondary loss of cell Ca ++ homoeostasis may also affect the relationship between Ca ++ leaks and Ca ++ extrusion across membranes of the sarcoplasmic reticulum. Exposure of mitochondria to excess Ca ++ causes them to swell and release intramitochondrial components. This reflects a sudden increase in the permeability of the mitochondrial inner membrane which allows the release of H + , Ca ++ , Mg ++ , and other low molecular weight components. There is strong evidence that mitochondrial dysfunction is an early recirculation event following long periods of ischaemia or ischaemia complicated by hyperglycaemia, qualifying as a direct cause of bioenergetic failure. 19 The effects of Ca ++ are summarized in Figure 3.1. D epression of Protein Synthesis N ormal protein synthesis is an early casualty of the ischaemic cascade. Normally the glutamate-induced Ca influx would result in transcription and translation of the immediate early genes (IEGs) c-fos and c-jun. These IEGs regulate the transcription of genes that code for proteins of repair. 19,23 These include the heat shock protein family, nerve growth factors, brain-derived neurotrophic factor, neurotropin-3 and enhanced expression of genes for glucose transports. 25 A block in translation due to focal or global ischaemia may thus affect the production of these stress proteins, trophic factors or enzymes and enhance ischaemic damage (Fig. 3.2). P ro g rammed Cell Death (PCD) PCD, or apoptosis when it occurs during development, is a process that weeds out approximately half of all neurones produced during neurogenesis, leaving only those that make useful functional connections to other neurones and end-organs. 25 It is a cell death characterized by membrane blebbing, cell shrinkage, nuclear condensation and fragmentation. There are considerable data that indicate that the mechanisms leading to apoptotic and necrotic forms of cell injury are very similar. 19 In apoptosis, cells and nuclei shrink, condense and fragment and are rapidly phagocytosed by macrophages. There is no leakage of cellular contents and thus no reactive response. During cell injury, cells swell, burst and necrose. The rupture o f Pa g e 40 Figure 3.1 Role of Ca ++ in neuronal injury (redrawn from Andrews RJ. Mechanisms of injury to the central nervous s y stem. Williams and Wilkins, Baltimore, 1996, pp 7 – 19 ) . intracellular contents into the ECF space provides a stimulus for a reactive response. 26 PCD is an active process which requires protein synthesis and is executed by the activation of 'death genes', 27 probably triggered by stimuli such as free radicals, Ca ++ accumulation, excitatory amino acids (glutamate), cytokines, antigens, hormones and apoptotic receptor signalling. 16,19 The apoptotic p rocess also involves changes in cell surface chemistry to enable recognition by macrophages. Much of the delayed neuronal necrosis that accounts for cell death hours or days subsequent to reperfusion after ischaemic injury appears to be caused by PCD, 25 and signs of apoptosis are often encountered in the penumbral zone of a focal ischaemic area. 19 Li p id Peroxidation and Free Radical Formation Free radicals are reactive chemical species that damage DNA, denature structural and functional proteins and result in peroxidation of membrane lipids. Free radicals are formed as a consequence of several processes including phospholipase activation by cytosolic Ca ++ , transitional metal reactions which involve free iron, arachidonate metabolism and oxidant production by inflammatory cells. These processes result in the formation of superoxide radicals, which are protonated in the ischaemic environment of the ischaemic brain to produce highly reactive hydroxyl radicals. Normally aerobic cells produce free radicals, which are then consumed by free radical scavengers, e.g. a-tocopherol and ascorbic acid, or appropriate enzymes, e.g. superoxide dismutase. In states where enzymatic processes are disrupted (ischaemia) or hyperoxia occurs (reperfusion), there may be excessive production of oxidants, in particular superoxide, hydrogen peroxide and the hydroxyl radical. These highly reactive oxidant species cause peroxidation of membrane phospholipids, oxidation of cellular proteins and nucleic acids and can attack both neuronal membranes as well as cerebral vasculature. 10 It appears that free radicals target cerebral microvasculature and that with other inflammatory mediators, e.g. platelet- activating factor, cause microvascular dysfunction and blood–brain–barrier disruption. 19 The brain is particularly vulnerable to oxidant attack due to intrinsically low levels of tissue antioxidant activity. Endothelial nitric oxide (NO) is normally associated with relaxation of vascular endothelium and in this setting may aid recovery from acute ischaemic insults. However, generation of neuronal NO, often triggered by EAAs, may result in cellular injury. One of the mechanisms of such injury involves the combination of NO with hydroxyl radicals to generate the highly reactive peroxynitrite species, which can result in molecular oxidant injury. Adhesion Molecule Ex p ression Acute brain injury is known to be associated with an inflammatory response 29 and there is evidence that leucocytes are involved in the production of brain swelling up to 10 days postinjury. Gupta et al have demonstrated that normal brain endothelial cells express low levels of leucocyte cell adhesion molecules (CAMs), and that these molecules are upregu- Pa g e 41 Figure 3.2 (1) Ischaemia causes axon terminals to release excitoxic glutamate, which opens N-methyl-D-aspartate (NMDA) channels, which allow calcium (Ca 2+ ) into the neurone. (2) Excess calcium, sodium and other indicators of ischaemia activate protein kinases which (3) phosphorylate immediate early gene (IEG) transcription factors. (4) These travel from the cytoplasm into the nucleus where they induce the transcription of IEG DNA (e.g. c-fos and c-jun), making IEG mRNA. (5) IEG mRNA leaves the nucleus and is translated at ribosomes into IEG protein (e.g. Fos and Jun families). (6) These gene-specific IEG products travel from the cytoplasm into the nucleus where they initiate transcription of DNA that codes for proteins of repair or the endonucleases that cause programmed cell death (PCD). (7) Repair or PCD mRNA then goes out to ribosomes in the cytoplasm where it is translated into proteins of repair (e.g. heat shock proteins) or PCD endonucleases. (8) Neurones that are distant from the ischaemic area are signalled to induce IEG transcription and translation (redrawn from reference 25 ). lated in a time-dependent manner following head injury in humans. 30 Activation of these CAMs recruits neutrophils to the damaged area, thereby occluding capillaries and enhancing free radical production. This has important implications for the potential strategies using antibodies that have been found experimentally. 31,32 Brain Oedema Two types of oedema occur: cytotoxic and vasogenic. Cytotoxic oedema is due to failure of ionic pumps with resultant ionic and fluid shifts. Vasogenic oedema is due to the release of mediators that damage endothelial cells, basement membrane matrix and/or glial cells, resulting in blood– b rain barrier breakdown. Specific mediators that have been involved in this process include arachidonic acid metabolites, free radicals, bradykinin and platelet-activating factor. The resulting oedema can cause increases in intracranial p ressure, with reduction in cerebral perfusion pressure (and cerebral ischaemia) and herniation of brain structures. Cerebral Protection Cerebral protection implies interventions designed to prevent pathophysiolgical processes from occurring, whilst cerebral resuscitation refers to intervention instituted after onset of the ischaemic insult, in orde r [...]... in mitochondria and cause efflux of Ca2+ and K+ into the cytosol and increases in levels of arachidonic acid, which is the rate-limiting substrate for prostanoid synthesis Increase of arachidonic acid (the commonest FFA), during cerebral insults, results in increased concentrations of the endoperoxides PGG2 and PGH2, which are the precursors of prostacyclin (PC/PGI2), and thromboxane A2 made in vascular... such periods of high ICP, the level of response may worsen with possible loss of control of the airway, exposing the patient to the further dangers of hypoxia and hypercarbia A waves were observed in 18 out of 76 patients in one study of head-injured patients and 11 of the 18 died.39 Tindall et al40 showed that a transient rise in PaCO2 often preceded the development of an A wave and Lassen and Christensen41... vasodilatation Major changes in CBF and therefore ICP can be produced by PaCO2 changes There is a straight line relationship between CBF and PaCO2: between the limits of 2. 6 and 10.6 kPa (20 –80 mmHg) PaCO2, CBF changes 2 ml/100 g brain for every mmHg change in PaCO2 The resultant change in cerebral blood volume (CBV) is 0.04 ml/100 g brain for every mmHg change in PaCO2 .22 When autoregulation is intact... physiology, 16th edn Appleton and Lange, NewYork 1993, pp 1–41 22 Siesjo BK Pathophysiology and treatment of focal cerebral ischaemia Part I Pathophysiology J Neurosurg 19 92; 77: 169–1 82 23 Fieschi C, Di Piero V, Lenzi GL et al Pathophysiology of ischemic brain disease Stroke 1990; 21 ( 12) : IV 9–11 24 Deshpande JK, Siesjo BK, Wieloch T Calcium accumulation and neuronal damage in the rat hippocampus following... Finkbeiner SM Therapeutic uses of magnesium sulphate in selected cases of cerebral ischaemia and seizure N Engl J Med 1988; 319: 122 4– 122 5 84 Vacanti FX, Ames A Mild hypothermia and Mg2+ protect against irreversible damage during CNS ischaemia Stroke 1984; 15: 695–698 85 Le Reille TE, Arvin B, Moucada C, Meldrum B The non-NMDA antagonists, NBQX and GYK1 524 66, protect against cortical and striatal cell loss... The effects of thiopentone on CMRO2 and CBF are well studied There is a dose-dependent fall in CMRO2 and a parallel fall in CBF until the electroencephalogram (EEG) is isoelectric.58 At this point the CMRO2 is about 50% of control values and no further fall in CMRO2 occurs if the thiopentone dosage is increased ICP falls with the CBF Propofol has similar effects to thiopentone on CMRO2 and CBF.59,60... Intraoperative neuro-protection Williams and Wilkins, Baltimore, 1996, pp 37–63 1 02 Egan RW, Paxton J, Kuehl FA Mechanism for irreversible self deactivation of prostaglandin synthetase J Biol Chem 1976; 25 7: 7 329 103 Van Den Kerckhoff W, Hossman KA, Hossman V No effect of prostacyclin on blood flow, regulation of blood flow and blood coagulation following global cerebral ischemia Stroke 1983; 14: 724 104 Hall... 4 .2 shows a CT scan of patient with an extradural haematoma and also shows a considerable shift of the midline structures The symptoms and signs produced by a supratentorial tumour depend on its rate of growth and whether it is Figure 4 .2 CT scan of a patient showing an extradural haematoma with considerable shift of the midline Page 54 developing in a relatively silent area of the brain or in one of. .. 89–95 25 Cottrell JE Possible mechanisms of pharmacological neuronal protection Symposium article J Neurosurg Anesthesiol 1995; 7 (1): 31–37 26 Alberts B, Bray D, Lewis J et al Differentiated cells and the maintenance of tissues In: Molecular biology of the cell, 3rd edn Garland, New York, 1994, pp 1174–1175 27 Stellar H Mechanisms and genes of cellular suicide Science 1995; 26 7: 1445–1449 28 Siesjo... Mechanisms of secondary brain injury Eur Anaesthesiol 1996; 13: 24 7 26 8 20 Lanier W, Stanglard K, Scheithauer BW et al The effects of dextrose infusion and head position on neurologic outcome after complete cerebral ischaemia in primates Examination of a model Anesthesiology 1987; 66: 39–48 21 Ganong WF Review of medical physiology The general and cellular basis of medical physiology, 16th edn Appleton and . increased concentrations of the endoperoxides PGG 2 and PGH 2 , which are the precursors of prostacyclin (PC/PGI 2 ), and thromboxane A 2 made in vascular endothelial cells and platelets respectively 1 – 41. 22 . Siesjo BK. Pathophysiology and treatment of focal cerebral ischaemia. Part I Pathophysiology. J Neurosurg 19 92; 77: 169 – 1 82. 23 . Fieschi C, Di Piero V, Lenzi GL et al. Pathophysiology of. Science 1995; 26 7: 1445 – 1449. 28 . Siesjo BK Pathophysiology and treatment of focal cerebral ischaemia. Part II Mechanisms of damage and treatment. J Neurosurg 19 92; 77: 337 – 354. 29 . Menon DK,