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Cerebral protection after cardiac arrest
Resuscitation. 22 ( 199 I ) 197-202
Elsevier Scientific
Publishers
Cerebral
197
Ireland
Ltd.
protection
after cardiac
arrest
A.R. Aitkenhead University
Arrest -
Cardiac
-
Hospiral.
Brain -
Queen :F Medical
Infarction
-
Cenrre. Noi~inglrunr NC7 2 UH ( U.K. )
Reperfusion
-
Protection
INTRODUCTION
Global ischaemia of the brain following cardiac arrest results in exhaustion of the available oxygen within 15 s and of brain glucose and adenosine within 5 min [I]. Cell membranes start to leak almost immediately, with the development of intracellular and interstitial oedema. In addition, the membrane calcium channels, which are voltage-dependent, open because of the alteration in the resting membrane potential, resulting in influx of Ca2+ into the cell. It is believed that Ca’+ triggers a cascade of events which result in neuronal damage. There is also an accumulation of acid, metabolites, free radicals, fatty acids and prostaglandins. If cardiopulmonary resuscitation is successful, there follows a period of reperfusion, which itself appears to damage cerebral cells. Electron microscopy reveals fairly evenly distributed changes in neurones within 5-7 min of circulatory arrest. If the circulation is not restored (e.g. in a decapitation model), it is claimed that the changes do not become irreversible for up to 60 min [2]. However, if reperfusion occurs, secondary changes occur which evolve into miliary microscopic cerebral infarcts [3]. A number of mechanisms have been proposed for the reperfusion phenomenon, sludging, capillary including red cell pinching, oedema, vasospasm, hypermetabolism, catecholamine release and acidosis, all of which impair delivery or utilisation of oxygen and result in a period of incomplete ischaemia. Incomplete ischaemia is known to be more harmful than complete ischaemia [4] because the continued, although reduced, supply of glucose is metabolised in the presence of an inadequate supply of oxygen, resulting in a rapid accumulation of lactate and a severe intracellular acidosis. Total cerebral blood flow (CBF) increases for a period of 15-30 min after an episode of global ischaemia [S]. CBF then declines below pre-arrest values [6], for reasons which are not totally understood, before increasing to supranormal levels again. However, for the reasons outlined above, the capillary circulation appears to be perfused inadequately even during the period of increased total CBF [7]. The period of increased CBF is accompanied by a transient increase in intracranial pressure (ICP), but ICP is seldom elevated greatly or for a prolonged period in adults unless the ischaemic period is very prolonged. O300-9572/91/$03.50 0 1991 Elsevier Printed and Published in Ireland
Scientific
Publishers
Ireland
Ltd.
198
The pattern of cerebral damge after global ischaemia is often bilateral and symmetrical, suggesting that the changes are not due primarily to systemic hypotension during and after resuscitation; if this were the case, the damage would occur predominantly in arterial border zones, and would often be asymmetrical. The damage may affect any area of the brain, but is commonest in the parieto-occipital and infratentorial tissues, and is more likely to affect grey matter than white matter. Fits are not uncommon, and may be due in part to influx of calcium into the cells. Severe neurological deficits are frequently associated with death before discharge from hospital, but up to 10% of long-term survivors suffer severe neurological damage [3]. DATA
REVIEW
Potential methods of ameliorating cerebral damage after cardiac arrest may be considered as those which confer a direct protective effect on the cells and those which are directed at an improvement of capillary blood flow. A number of methods which have been investigated may affect both mechanisms. As ICP is seldom elevated unless secondary deterioration occurs [3], methods of ICP control which may benefit patients with other types of cerebral injury may be of little value, and have not been found to be of benefit after cardiac arrest. Very few controlled trials of potentially beneficial therapies have been undertaken in man, and in most cases it is necessary to consider the potential benefits on the basis of experimental data from animal models. There are inherent risks in making such extrapolations. Artificial
ventilation
Artificial ventilation is essential during cardiopulmonary resuscitation, and may be required afterwards to maintain normal arterial oxygen and carbon dioxide tensions, particularly if pulmonary oedema is present, if pulmonary aspiration has occurred or if large quantities of bicarbonate have been administered. Hyperventilation is an effective means of abruptly reducing CBF and ICP, but its effect is temporary. There is evidence from an animal model that elective artificial ventilation after global ischaemia has no influence on neurological outcome [8]. There are no comparable studies in man, although artificial ventilation has been shown to be of no benefit in patients with acute stroke [9] (in whom the inverse steal phenomenon might be of more importance than after global ischaemia) or in patients with severe head injury [lo] (in whom control of ICP is of more importance). Hypothermia
Hypothermia reduces cerebral oxygen requirements by decreasing cerebral metabolism associated with both function and structural integrity of brain cells. It is the only method of cerebral protection which has been proved to be beneficial during circulatory arrest, and is used routinely for this purpose during cardiopulmonary bypass surgery. However, its efficacy after circulatory arrest is less clear. Its prolonged use is associated with dysrhythmias, increased blood viscosity, reduced tissue blood flow, increased risk of infection and stress ulceration [3]. No clinical trials have been undertaken to evaluate its use in man.
Intravenous anaesthetic
agents
The use of barbiturates was advocated after global ischaemia because of a number of potentially useful properties. The barbiturates decrease cerebral metabolic rate, CBF and ICP, may promote the inverse steal phenomenon and have been shown experimentally to be free radical scavengers. However, unlike hypothermia, the barbiturates (in common with other anaesthetic agents) reduce only the metabolism associated with cell function [ 111,and their free radical scavenging activity was shown in experimental studies to be unrelated to any protective effect on the brain [12]. Following global ischaemia, barbiturates have been shown to be of no benefit in terms of improved neurological outcome in animals [8] or in respect of either survival or neurological recovery in man [ 131. The barbiturates do reduce neurological sequelae after cardiopulmonary bypass [ 141, but only if administered before ischaemia has occurred; it is likely that the neurological sequelae which are influenced by barbiturate administration are the result of multiple focal embolic lesions rather than global ischaemia. Control of blood glucose
Animal experiments have demonstrated that increases in blood glucose concentration aggravate neurological damage after cerebral ischaemia [4]. The most likely explanation is that increased glucose delivery to the poorly perfused brain results in increased lactate production and a greater degree of intracellular acidosis. Impaired neurological recovery in man has been noted after cardiac arrest in patients with a high blood sugar concentration [15]. It is thought that a blood sugar concentration in excess of 13.5 mmol/l is potentially harmful in this respect. In a primate model, it has been demonstrated [16] that neurological outcome was significantly worse after global ischaemia in animals which received glucose by infusion immediately before the insult than in those given sodium acetate solution, despite the fact that blood glucose concentration was less than 11 mmol/l in all animals. Further, there was a significant correlation between blood glucose concentration and the degree of neurological damage. Calcium entry blockers
These drugs have been investigated because of the role of calcium influx into cells in the mediation of cerebral injury. In addition, some members of the group delay or abolish the postischaemic hypoperfusion state [17]. Nimodipine has been shown to be beneficial in reducing morbidity from cerebral vasospasm after subarachnoid haemorrhage [ 181and to reduce mortality and morbidity in acute stroke [ 191. However, in animal experiments, nimodipine was not effective in dogs when administered after a period of global ischaemia, although it was beneficial if administered prior to the ischaemic insult [17]. In a rigidly controlled experiment in monkeys [20], nimodipine produced a statistically significant improvement in neurological recovery when administered after global ischaemia. However, three of the 11 animals which received nimodipine were severely damaged; the results were not clear-cut. In these experiments, blood glucose was not controlled and a subsequent study using the same model [ 161demonstrated a much clearer improvement in neurological outcome from control of blood sugar than had been apparent in the nimodipine experiments.
200
Lidoflazine produces less effect than nimodipine pears to improve neurological outcome after cardiac fibrillation is present [21]. In primates, lidoflazine outcome after global ischaemia [22]. Flunarizine vestigated but with poor results.
on postischaemic CBF, and aparrest in dogs only if ventricular does not influence neurological and nicardipine have been in-
Therapy directed at free radicals
There is in vitro evidence that fatty acids released during ischaemia may lead to the formation of free radicals such as superoxide, hydroxyl radicals and hydrogen peroxide, which result in membrane damage. It has been suggested that formation of free radicals occurs by way of reactions catalysed by iron [23]. However, the iron chelator desferrioxamine does not prevent neurological outcome in animals subjected to cerebral ischaemia (241. Attempts to increase free radical removal by administration of superoxide dismutase and catalase have also been unsuccessful [25]. It is not certain whether these substances cross the blood-brain barrier, so that the failure cannot necessarily be ascribed to lack of action at a cellular level. Excitatory
amino acid receptor antagonism
There is some evidence that receptor activation mediated by excitatory amino acids (EAA), particularly L-glutamate and L-aspartate, may be involved in the production of postischaemic neuronal necrosis [26]. The regions of the brain known to be most susceptible to ischaemic damage have a high concentration of EAA receptors. EAA concentrations in these areas increase after an ischaemic episode and prolonged stimulation of EAA receptors results in neuronal death. Most attention has centred on the N-methyl-D-aspartate (NMDA) class of glutamate receptor. However, there has been little success in experimental attempts to reduce neurological damage by administration of NMDA receptor antagonists. Techniques to improve capillary flow
Systemic hypotension frequently follows resuscitation from cardiac arrest. If the arteriolar and capillary circulations are subject to the ‘reperfusion’ changes outlined above, and have lost the capacity to autoregulate, then perfusion is likely to be pressure-dependent. It would seem that restoration of normotension, or induction of moderate arterial hypertension, as rapidly as possible might improve the capillary circulation and minimise neuronal damage. In addition, specific measures to increase CBF or to improve capillary flow itself might be valuable. The induction of moderate hypertension together with haemodilution and heparinisation for 6 h after fibrillatory cardiac arrest in dogs has been shown to produce significantly better neurological outcome than in control animals [27]. An improvement in neurological recovery after global ischaemia in rats given naloxone has been attributed to maintenance of cardiac output and cerebral blood flow [28]. CBF has been shown to increase with haemodilution in damaged brain, although in normal brain CBF remains relatively constant because of ‘viscosity autoregulation’ [29]. Dopamine has been shown to increase CBF and hasten return of somatosensory evoked potentials in dogs subjected to cerebral ischaemia even at doses which had no effect on systemic arterial pressure (5-10 &kg per min) [30]. Recovery also oc-
201
curred when arterial pressure was elevated slightly (S---l5 mmHg) by higher doses (20-30 pg/kg per min), but was impaired at very high doses when arterial pressure was raised to 2&30’S above baseline. CONCLUSIONS
Because of the large number of confounding variables, there have been very few clinical studies of therapeutic modalities designed to ameliorate cerebral damage after cardiac arrest. At present, there is no evidence that any specific form of treatment improves cerebral outcome in man. Hypoxaemia, hypercapnia and hypotension in the post-arrest period are likely to exacerbate cerebral damage, and appropriate steps should be taken to optimise gas exchange and cerebra1 perfusion by conventional intensive care techniques; this may include the use of mechanical ventilation, but the improvement in oxygenation of blood must be balanced against the reduction in oxygen delivery from reduced cardiac output. Significantly raised intracranial pressure is uncommon after cardiac arrest in adults. If there is clinical evidence of intracranial hypertension, intracranial pressure should be monitored and, if appropriate, controlled; the possibility of a mass lesion as the cause of intracranial hypertension should be borne in mind. It may be prudent to prevent hyperglycaemia. REFERENCES B. Ljunggren. H. Schutz and B.K. Siesjo, Changes in energy state and acid-base parameters rat brain during complete compression ischemia. Brain Res., 73 (1974) 277-289.
IO II
12 13
of the
K.A. Hossmann and P. Kleihues. Reversibility of ischemic brain damage, Arch. Neural., 29 (1973) 375-379. P. Safar, Resuscitation after brain &hernia. In: Brain failure and resuscitation. Editors: A. Grenvik and P. Safar. Clinics in Critical Care Medicine 2. Churchill Livingstone. New York. 1981. pp. 155-184. S. Rehncrona, I. Rosen and B.K. Siesjii. Excessive cellular acidosis: an important mechanism of neuronal damage in the brain? Acta Physiol. Stand.. I IO (1980) 425427. K.A. Hossmann. Lechtabe-Griiter and V. Hossman, The role of cerebral blood flow for the recovery of the brain after prolonged &hernia, Z. Neural., 204 (1973) 281-299. J.E. Beckstead, W.A. Tweed, J. Lee and W.L MacKeen. Cerebral blood flow and metabolism in man following cardiac arrest, Stroke, 9 (1978) 569-572. A. Ames. L. Wright, M. Kowada. J.M. Thurston and G. Majno, Cerebral ischemia II. The no-reflow phenomenon. Am. J. Pathol.; 52 (1968) 437453. S.E. Gisvold, P. Safar, H.H.L. Hendricks, G. Rao. J. Moossy and H. Alexander. Thiopental after global brain &hernia in pigtailed monkeys, Anesthesiology, 60 (1984) 88-96. M.S. Christensen. O.B. Paulson and J. Olesen et al. Cerebral apoplexy (stroke) treated with or without prolonged artificial ventilation. I. Cerebral circulation. clinical course. and cause of death, Stroke, 4 (1973) 568-631. G.J. Gelpke, R. Braakman. J.D. Habbema and J. Hilden. Comparison of outcome in two series of patients with severe head injuries, J. Neurosurg.. 59 (1983) 745-750. J.D. Michenfelder. The in vivo effects of massive concentrations of anesthetics on canine cerebral metabolism. In: Molecular Mechanisms of Anesthesia. Editor: B.R. Fink. Raven Press. New York, 1983, p. 537. P.A. Steen and J.D. Michenfelder, Barbiturate protection in tolerant and non-tolerant hypoxic mice: comparison with hypothermic protection, Anesthesiology, 50 (1979) 404-408. N.S. Abramson, P. Safar and K.M. Detre. et a)., Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest, N. Engl. J. Med., 314 (1986) 397-403.
202
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25
26 27 28 29 30
N.A. Nussmeier, C. Arlund and S. Slogoff, Neuropsychiatric complications after cardiopulmonary bypass: cerebral protection by a barbiturate, Anesthesiology. 64 (1986) 165-170. W.T. Longstreth and T.S. Inui, High blood glucose level on hospital admission and poor neurological recovery after cardiac arrest, Ann. Neural., I5 (1984) 59-63. W.L. Lamer, K.J. Stangland, B.W. Scheithauer, J.H. Milde and J.D. Michenfeider, The effects of dextrose infusion and head position on neurologic outcome after complete cerebral ischemia in primates: examination of a model, Anesthesiology, 66 (1987) 3948. P.A. Steen. L.A. Newberg, J.H. Milde and J.D. Michenfelder, Cerebral blood flow and neurologic outcome when nimodipine is given after complete cerebral ischemia in the dog, J. Cerebral Blood Flow Metab., 4 (1984) 82-87. G.S Allen, H.S. Ahn and T.J. Preziosi, et al.. Cerebral arterial spasm-a controlled trial of nimodipine in patients with subarachnoid hemorrhage, N. Engl. J. Med., 308 (1983) 619-624. H.J. Gelmers, K. Gorter. C.J. deWeerdt and H.J. Wiezer, A controlled trial of nimodipine in acute ischemic stroke, N. Engl. J. Med., 318 (1988) 203-7. P.A. Steen, SE. Gisvold. J.H. Milde, L.A. Newberg, B.W. Scheithauer. W.L. Lanier and J.D. Michenfelder, Nimodipine improves outcome when given after complete cerebral &hernia in primates, Anesthesiology, 62 (1985) 406-414. P. Vaagenes, R. Cantadore, P. Safar and H. Alexander, Effect of lidoflazine on neurologic outcome after cardiac arrest in dogs, Anesthesiology, 59 (1983) AIOO. J.E. Fleischer, W.L. Lanier, J.H. Milde and J.D. Michenfelder. Lidotlazine does not improve neurologic outcome when administered after complete cerebral ischemia in primates. J. Cerebral Blood Flow Metab., 7 (1987) 366371. B.C. White, S.D. Aust, K.E. Arfors and L.D. Aronson, Brain injury by ischemic anoxia: hypothesis extension - a tale of two ions? Ann. Emerg. Med.. I3 (1984) 862-867. J.E. Fleischer, W.L. Lanier, J.H. Milde and J.D. Michenfelder. Failure of desferoxamine. an iron chelator, to improve neurologic outcome following complete cerebral ischemia in dogs, Stroke, I8 (1987) 126127. M. Forsman. J.E. Fleischer, J.H. Milde. P.A. Steen and J.D. Michenfelder, Superoxide dismutase and catalase failed to improve neurologic outcome after complete cerebral ischemia in the dog, Acta Anaesthesiol. Stand.. 32 (1988) 152-155. S.M. Rothman and J.W. Olney, Excitotoxicity and the NMDA receptor, Trends Neurosci.. IO (1987) 299-302. P. Safar. W. Stezoski and E.M. Nemoto, Amelioration of brain damage after I2 minute cardiac arrest in dogs, Arch. Neural.. 33 (1976) 91-5. D.S. Baskin, Y. Hosobuchi and J.C. Grevel. Treatment of experimental stroke with opiate antagonists. Effects on neurologic function. infarct size and survival. J. Neurosurg., 64 (1986) 99-103. J.P. Muizelaar. E.P. Wei. H.A. Kontos and D.P. Becker, Cerebral blood flow is regulated by changes in blood pressure and viscosity alike, Stroke, I7 (1986) 44-48. Y. Nakagawa, H. Konomoto and H. Abe. Effects of dopamine on cortical blood flow and somatosensory evoked potentials in the acute stage of cerebral &hernia. Stroke. I7 (1986) 25-30.
Elsevier Scientific
Publishers
Cerebral
197
Ireland
Ltd.
protection
after cardiac
arrest
A.R. Aitkenhead University
Arrest -
Cardiac
-
Hospiral.
Brain -
Queen :F Medical
Infarction
-
Cenrre. Noi~inglrunr NC7 2 UH ( U.K. )
Reperfusion
-
Protection
INTRODUCTION
Global ischaemia of the brain following cardiac arrest results in exhaustion of the available oxygen within 15 s and of brain glucose and adenosine within 5 min [I]. Cell membranes start to leak almost immediately, with the development of intracellular and interstitial oedema. In addition, the membrane calcium channels, which are voltage-dependent, open because of the alteration in the resting membrane potential, resulting in influx of Ca2+ into the cell. It is believed that Ca’+ triggers a cascade of events which result in neuronal damage. There is also an accumulation of acid, metabolites, free radicals, fatty acids and prostaglandins. If cardiopulmonary resuscitation is successful, there follows a period of reperfusion, which itself appears to damage cerebral cells. Electron microscopy reveals fairly evenly distributed changes in neurones within 5-7 min of circulatory arrest. If the circulation is not restored (e.g. in a decapitation model), it is claimed that the changes do not become irreversible for up to 60 min [2]. However, if reperfusion occurs, secondary changes occur which evolve into miliary microscopic cerebral infarcts [3]. A number of mechanisms have been proposed for the reperfusion phenomenon, sludging, capillary including red cell pinching, oedema, vasospasm, hypermetabolism, catecholamine release and acidosis, all of which impair delivery or utilisation of oxygen and result in a period of incomplete ischaemia. Incomplete ischaemia is known to be more harmful than complete ischaemia [4] because the continued, although reduced, supply of glucose is metabolised in the presence of an inadequate supply of oxygen, resulting in a rapid accumulation of lactate and a severe intracellular acidosis. Total cerebral blood flow (CBF) increases for a period of 15-30 min after an episode of global ischaemia [S]. CBF then declines below pre-arrest values [6], for reasons which are not totally understood, before increasing to supranormal levels again. However, for the reasons outlined above, the capillary circulation appears to be perfused inadequately even during the period of increased total CBF [7]. The period of increased CBF is accompanied by a transient increase in intracranial pressure (ICP), but ICP is seldom elevated greatly or for a prolonged period in adults unless the ischaemic period is very prolonged. O300-9572/91/$03.50 0 1991 Elsevier Printed and Published in Ireland
Scientific
Publishers
Ireland
Ltd.
198
The pattern of cerebral damge after global ischaemia is often bilateral and symmetrical, suggesting that the changes are not due primarily to systemic hypotension during and after resuscitation; if this were the case, the damage would occur predominantly in arterial border zones, and would often be asymmetrical. The damage may affect any area of the brain, but is commonest in the parieto-occipital and infratentorial tissues, and is more likely to affect grey matter than white matter. Fits are not uncommon, and may be due in part to influx of calcium into the cells. Severe neurological deficits are frequently associated with death before discharge from hospital, but up to 10% of long-term survivors suffer severe neurological damage [3]. DATA
REVIEW
Potential methods of ameliorating cerebral damage after cardiac arrest may be considered as those which confer a direct protective effect on the cells and those which are directed at an improvement of capillary blood flow. A number of methods which have been investigated may affect both mechanisms. As ICP is seldom elevated unless secondary deterioration occurs [3], methods of ICP control which may benefit patients with other types of cerebral injury may be of little value, and have not been found to be of benefit after cardiac arrest. Very few controlled trials of potentially beneficial therapies have been undertaken in man, and in most cases it is necessary to consider the potential benefits on the basis of experimental data from animal models. There are inherent risks in making such extrapolations. Artificial
ventilation
Artificial ventilation is essential during cardiopulmonary resuscitation, and may be required afterwards to maintain normal arterial oxygen and carbon dioxide tensions, particularly if pulmonary oedema is present, if pulmonary aspiration has occurred or if large quantities of bicarbonate have been administered. Hyperventilation is an effective means of abruptly reducing CBF and ICP, but its effect is temporary. There is evidence from an animal model that elective artificial ventilation after global ischaemia has no influence on neurological outcome [8]. There are no comparable studies in man, although artificial ventilation has been shown to be of no benefit in patients with acute stroke [9] (in whom the inverse steal phenomenon might be of more importance than after global ischaemia) or in patients with severe head injury [lo] (in whom control of ICP is of more importance). Hypothermia
Hypothermia reduces cerebral oxygen requirements by decreasing cerebral metabolism associated with both function and structural integrity of brain cells. It is the only method of cerebral protection which has been proved to be beneficial during circulatory arrest, and is used routinely for this purpose during cardiopulmonary bypass surgery. However, its efficacy after circulatory arrest is less clear. Its prolonged use is associated with dysrhythmias, increased blood viscosity, reduced tissue blood flow, increased risk of infection and stress ulceration [3]. No clinical trials have been undertaken to evaluate its use in man.
Intravenous anaesthetic
agents
The use of barbiturates was advocated after global ischaemia because of a number of potentially useful properties. The barbiturates decrease cerebral metabolic rate, CBF and ICP, may promote the inverse steal phenomenon and have been shown experimentally to be free radical scavengers. However, unlike hypothermia, the barbiturates (in common with other anaesthetic agents) reduce only the metabolism associated with cell function [ 111,and their free radical scavenging activity was shown in experimental studies to be unrelated to any protective effect on the brain [12]. Following global ischaemia, barbiturates have been shown to be of no benefit in terms of improved neurological outcome in animals [8] or in respect of either survival or neurological recovery in man [ 131. The barbiturates do reduce neurological sequelae after cardiopulmonary bypass [ 141, but only if administered before ischaemia has occurred; it is likely that the neurological sequelae which are influenced by barbiturate administration are the result of multiple focal embolic lesions rather than global ischaemia. Control of blood glucose
Animal experiments have demonstrated that increases in blood glucose concentration aggravate neurological damage after cerebral ischaemia [4]. The most likely explanation is that increased glucose delivery to the poorly perfused brain results in increased lactate production and a greater degree of intracellular acidosis. Impaired neurological recovery in man has been noted after cardiac arrest in patients with a high blood sugar concentration [15]. It is thought that a blood sugar concentration in excess of 13.5 mmol/l is potentially harmful in this respect. In a primate model, it has been demonstrated [16] that neurological outcome was significantly worse after global ischaemia in animals which received glucose by infusion immediately before the insult than in those given sodium acetate solution, despite the fact that blood glucose concentration was less than 11 mmol/l in all animals. Further, there was a significant correlation between blood glucose concentration and the degree of neurological damage. Calcium entry blockers
These drugs have been investigated because of the role of calcium influx into cells in the mediation of cerebral injury. In addition, some members of the group delay or abolish the postischaemic hypoperfusion state [17]. Nimodipine has been shown to be beneficial in reducing morbidity from cerebral vasospasm after subarachnoid haemorrhage [ 181and to reduce mortality and morbidity in acute stroke [ 191. However, in animal experiments, nimodipine was not effective in dogs when administered after a period of global ischaemia, although it was beneficial if administered prior to the ischaemic insult [17]. In a rigidly controlled experiment in monkeys [20], nimodipine produced a statistically significant improvement in neurological recovery when administered after global ischaemia. However, three of the 11 animals which received nimodipine were severely damaged; the results were not clear-cut. In these experiments, blood glucose was not controlled and a subsequent study using the same model [ 161demonstrated a much clearer improvement in neurological outcome from control of blood sugar than had been apparent in the nimodipine experiments.
200
Lidoflazine produces less effect than nimodipine pears to improve neurological outcome after cardiac fibrillation is present [21]. In primates, lidoflazine outcome after global ischaemia [22]. Flunarizine vestigated but with poor results.
on postischaemic CBF, and aparrest in dogs only if ventricular does not influence neurological and nicardipine have been in-
Therapy directed at free radicals
There is in vitro evidence that fatty acids released during ischaemia may lead to the formation of free radicals such as superoxide, hydroxyl radicals and hydrogen peroxide, which result in membrane damage. It has been suggested that formation of free radicals occurs by way of reactions catalysed by iron [23]. However, the iron chelator desferrioxamine does not prevent neurological outcome in animals subjected to cerebral ischaemia (241. Attempts to increase free radical removal by administration of superoxide dismutase and catalase have also been unsuccessful [25]. It is not certain whether these substances cross the blood-brain barrier, so that the failure cannot necessarily be ascribed to lack of action at a cellular level. Excitatory
amino acid receptor antagonism
There is some evidence that receptor activation mediated by excitatory amino acids (EAA), particularly L-glutamate and L-aspartate, may be involved in the production of postischaemic neuronal necrosis [26]. The regions of the brain known to be most susceptible to ischaemic damage have a high concentration of EAA receptors. EAA concentrations in these areas increase after an ischaemic episode and prolonged stimulation of EAA receptors results in neuronal death. Most attention has centred on the N-methyl-D-aspartate (NMDA) class of glutamate receptor. However, there has been little success in experimental attempts to reduce neurological damage by administration of NMDA receptor antagonists. Techniques to improve capillary flow
Systemic hypotension frequently follows resuscitation from cardiac arrest. If the arteriolar and capillary circulations are subject to the ‘reperfusion’ changes outlined above, and have lost the capacity to autoregulate, then perfusion is likely to be pressure-dependent. It would seem that restoration of normotension, or induction of moderate arterial hypertension, as rapidly as possible might improve the capillary circulation and minimise neuronal damage. In addition, specific measures to increase CBF or to improve capillary flow itself might be valuable. The induction of moderate hypertension together with haemodilution and heparinisation for 6 h after fibrillatory cardiac arrest in dogs has been shown to produce significantly better neurological outcome than in control animals [27]. An improvement in neurological recovery after global ischaemia in rats given naloxone has been attributed to maintenance of cardiac output and cerebral blood flow [28]. CBF has been shown to increase with haemodilution in damaged brain, although in normal brain CBF remains relatively constant because of ‘viscosity autoregulation’ [29]. Dopamine has been shown to increase CBF and hasten return of somatosensory evoked potentials in dogs subjected to cerebral ischaemia even at doses which had no effect on systemic arterial pressure (5-10 &kg per min) [30]. Recovery also oc-
201
curred when arterial pressure was elevated slightly (S---l5 mmHg) by higher doses (20-30 pg/kg per min), but was impaired at very high doses when arterial pressure was raised to 2&30’S above baseline. CONCLUSIONS
Because of the large number of confounding variables, there have been very few clinical studies of therapeutic modalities designed to ameliorate cerebral damage after cardiac arrest. At present, there is no evidence that any specific form of treatment improves cerebral outcome in man. Hypoxaemia, hypercapnia and hypotension in the post-arrest period are likely to exacerbate cerebral damage, and appropriate steps should be taken to optimise gas exchange and cerebra1 perfusion by conventional intensive care techniques; this may include the use of mechanical ventilation, but the improvement in oxygenation of blood must be balanced against the reduction in oxygen delivery from reduced cardiac output. Significantly raised intracranial pressure is uncommon after cardiac arrest in adults. If there is clinical evidence of intracranial hypertension, intracranial pressure should be monitored and, if appropriate, controlled; the possibility of a mass lesion as the cause of intracranial hypertension should be borne in mind. It may be prudent to prevent hyperglycaemia. REFERENCES B. Ljunggren. H. Schutz and B.K. Siesjo, Changes in energy state and acid-base parameters rat brain during complete compression ischemia. Brain Res., 73 (1974) 277-289.
IO II
12 13
of the
K.A. Hossmann and P. Kleihues. Reversibility of ischemic brain damage, Arch. Neural., 29 (1973) 375-379. P. Safar, Resuscitation after brain &hernia. In: Brain failure and resuscitation. Editors: A. Grenvik and P. Safar. Clinics in Critical Care Medicine 2. Churchill Livingstone. New York. 1981. pp. 155-184. S. Rehncrona, I. Rosen and B.K. Siesjii. Excessive cellular acidosis: an important mechanism of neuronal damage in the brain? Acta Physiol. Stand.. I IO (1980) 425427. K.A. Hossmann. Lechtabe-Griiter and V. Hossman, The role of cerebral blood flow for the recovery of the brain after prolonged &hernia, Z. Neural., 204 (1973) 281-299. J.E. Beckstead, W.A. Tweed, J. Lee and W.L MacKeen. Cerebral blood flow and metabolism in man following cardiac arrest, Stroke, 9 (1978) 569-572. A. Ames. L. Wright, M. Kowada. J.M. Thurston and G. Majno, Cerebral ischemia II. The no-reflow phenomenon. Am. J. Pathol.; 52 (1968) 437453. S.E. Gisvold, P. Safar, H.H.L. Hendricks, G. Rao. J. Moossy and H. Alexander. Thiopental after global brain &hernia in pigtailed monkeys, Anesthesiology, 60 (1984) 88-96. M.S. Christensen. O.B. Paulson and J. Olesen et al. Cerebral apoplexy (stroke) treated with or without prolonged artificial ventilation. I. Cerebral circulation. clinical course. and cause of death, Stroke, 4 (1973) 568-631. G.J. Gelpke, R. Braakman. J.D. Habbema and J. Hilden. Comparison of outcome in two series of patients with severe head injuries, J. Neurosurg.. 59 (1983) 745-750. J.D. Michenfelder. The in vivo effects of massive concentrations of anesthetics on canine cerebral metabolism. In: Molecular Mechanisms of Anesthesia. Editor: B.R. Fink. Raven Press. New York, 1983, p. 537. P.A. Steen and J.D. Michenfelder, Barbiturate protection in tolerant and non-tolerant hypoxic mice: comparison with hypothermic protection, Anesthesiology, 50 (1979) 404-408. N.S. Abramson, P. Safar and K.M. Detre. et a)., Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest, N. Engl. J. Med., 314 (1986) 397-403.
202
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17
18 I9 20
21 22
23 24
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