PHYSIOLOGY OF CEREBRAL BLOOD FLOW

Br.J. Anaesth. (1976), 48, 719

PHYSIOLOGY OF CEREBRAL BLOOD FLOW N. A. LASSEN AND M.

NIELS A.

LASSEN, M.D.; M.

STIG CHRISTENSEN,

M.D.;

Department of Clinical Physiology, Bispebjerg Hospital, DK-2400 Copenhagen NV, and Department of Anaesthesiology, Copenhagen Municipal Hospital at Hvidovre, DK-2650 Hvidovre, Denmark. Correspondence to M. S. C. at Copenhagen Municipal Hospital.

normal man increases CBF, in the critical cases can be expected to increase ICP and also to aggravate mass displacement, probably also via intracranial blood volume effects. To avoid painful stimuli even in the comatose state is, in the opinion of some neuroanaesthetists, a basic principle to which the present line of argument gives substance. MEASUREMENT OF CEREBRAL BLOOD FLOW

With the introduction of the nitrous oxide method (Kety and Schmidt, 1945), quantitative determination of CBF in each hemisphere was made possible in unanaesthetized man for the first time. This technique allowed simultaneous studies of the cerebral (hemispheric) metabolism to be performed. Lassen and Munck (1955) modified the classical Kety-Schmidt technique by substituting the inhalation of a radioactive inert gas (krypton-85) in place of nitrous oxide. By injection of fluid containing dissolved krypton85 into the common carotid artery, a regional flow determination was made possible (Lassen and Ingvar, 1961). The advent of external counting led to an improvement in the method, making it especially suitable for clinical use, following the injection of xenon-133 in saline into the internal carotid artery (Heedt-Rasmussen, 1965). Furthermore, the use of collimated scintillation detectors allowed flow measurement in small, circumscribed regions of the brain. At present a regional cerebral bloodflow(rCBF) technique is available allowing simultaneous measurement in 256 regions of a hemisphere (Sveinsdottir and Lassen, 1973). The clearance curves obtained after i.a. injection may be analysed in three different ways: (1) stochastic analysis ("height over area") to infinity will give the true flow value, whereas the same analysis performed on that part of the curve covering the first 10 min will overestimate the flow by about 15%; (2) compartmental analysis ("exponential peeling") of the normally bi-exponential curve discloses a fast clearance component (attributed to grey matter), and a slow component (attributed to white matter); and (3) the slope of the first minute of the logarithmically displayed clearance curve ("initial slope index") that gives a flow equivalent which is 20-30% lower than the grey matter flow, and has a

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Knowledge of the physiology and pathophysiology of the cerebral blood flow (CBF) is essential for the proper treatment of patients with major intracranial disease, and for neuroanaesthesia in particular. To give substance to this statement is the purpose of the present paper, but, before going into the details regarding CBF and its regulation, it may be appropriate to stress some general relations: cerebral vasodilator stimuli tend to increase intracranial blood volume and hence intracranial pressure (JCP). These effects are much enhanced in patients with spaceoccupying intracranial lesions in whom the induced ICP increase may cause generalized cerebral ischaemia. In addition, the increase in cerebral blood volume may aggravate mass displacement and hence cause localized compression and tissue ischaemia. The relations outlined above illustrate a basic principle. A cerebral vasodilator stimulus, which in the normal brain will cause an increase in CBF, may in patients with such brain diseases as tumour, traumatic oedema or haemorrhage produce a paradoxical decrease in CBF in the whole brain or in parts of the brain, a so-called "steal" effect. The opposite effect is equally typical, namely a cerebral vasoconstrictor stimulus which in normal man reduces CBF may in such patients be found paradoxically to increase CBF, the so-called "inverse steal" effect. Thus, information gained from studies of CBF in normal animals or in normal man must be applied with great caution to certain neuroanaesthesiological conditions. To give a specific example, let it be recalled that halothane is, just as other volatile anaesthetic agents, a cerebral vasodilator. How, then, does halothane influence cerebral blood flow? In normal brain tissue it increases CBF, but in the disease states mentioned it may paradoxically be found to decrease CBF and to cause critical ischaemia because of the effect on ICP. Similarly pain, which in

S. CHRISTENSEN

720

BRITISH JOURNAL OF ANAESTHESIA more energy is used for ion-pumping and transmitter synthesis, more energy is produced by oxidative glucose combustion and more energy is supplied by an increase in blood flow, all at a strictly regional level. This pattern is well known in other organs, for example in skeletal muscle, where local hyperaemia is found following local contractions and local metabolic stimulation. In disease states, the principle of metabolic regulation of CBF is also well established. The enhanced function, oxygen uptake and bloodflowduring epileptic seizure is a prime example of this interrelationship (fig. 1). Because the increase in regional tissue metabolism is met by an increase in CBF, the jugular AUTOREGUIATORY

(coma)

(seizure) tt < nerve cellll activity CHEMICAL

pertusion pres NEUROGENIC

REGULATION OF CEREBRAL BLOOD FLOW

Metabolic regulation The normal brain has a high and stable overall metabolic rate both in wakefulness and in sleep, and a relatively high and constant global (hemispheric) blood flow of about 50 ml/100 g of brain tissue each minute. This picture of constancy of energy supply and of energy utilization has long been known to be incomplete, however, because at a regional level, within circumscribed brain regions, the pattern found in other organs can also be demonstrated in the brain: enhanced tissue function implies enhancement of metabolic activity and of blood supply. Recently this pattern, which had previously been observed in animal studies, has been shown in man also. During simple voluntary muscle contraction, Olesen (1971) found a regional CBF increase in the corresponding (contralateral) sensorimotor cortical hand area. The regionalflowincrease amounted to 50% or even 100%, and, as subsequently demonstrated by Raichle (1975), the regional oxygen uptake is also increased. These findings have established the general pattern of metabolic regulation of CBF as a mechanism operating under strictly physiological conditions. Thus, enhanced neuronal work in a cortical region apparently does not merely constitute a reorganization of local nervous activities, but entails an enhanced overall activity in the region involved. It means that, when the brain performs work in the ordinary physical sense,

Drain LCr pH

I level of activity of svmpat f c penvascular nerves'*

FIG. 1. Schematic representation of the different modes by which the cerebral blood flow (CBF) is controlled. ECF = extracellular fluid.

venous oxygen tension and that of the tissue are maintained relatively constant during increased nervous activity. In fact, both tensions increase as would be expected if the oxygen tension gradients (the driving force for oxygen supply) are to increase without a decrease in Po 2 in the tissue areas which are most distant from the capillaries. As the oxygen tension and content of regional venous blood increase during states of enhanced metabolic activity, it means that the percentage increase in regional CBF overshoots the increase in regional oxygen utilization. It also means that oxygen lack at the sites measured does not constitute a trigger to adjust flow to metabolism. What can it be, then, that couples flow to metabolism? This fundamental question cannot be answered. At present two main possibilities are being considered, namely H+ and K+ concentration changes in the extracellular fluid surrounding the brain arterioles. Certain states of depression of cortical functional activity are conventionally also taken to exemplify the

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linear correlation to the value found by stochastic analysis of the curve from the first 10 min clearance. Despite the apparent differences between the KetySchmidt inert gas inhalation method and the LassenIngvar inert gas injection method, they are based on the same principles. Both yield a measure of the mean transit time (t) of the tracer gas in the brain. Both use the same assumptions for calculating flow from t, namely knowledge of the brain : blood solubility ratio for the gas (A). The equations are the same as also are the normal values for cerebral blood flow. It should be stressed that both methods express CBF in terms of flow rate (ml blood/min) per 100 g of perfused brain tissue. This latter point means that the methods are insensitive to unperfused tissue areas, namely to total ischaemia. There are a number of other methods, but many of these can only be used in animals, and have contributed little to the development of the concepts that relate to clinical problems which the present paper aims at clarifying.

PHYSIOLOGY OF CEREBRAL BLOOD FLOW

Pain and anxiety. In normal man painful stimuli cause a large increase in CBF (Ingvar, 1975) and anxiety appears to do the same for unknown reasons perhaps related to increase in blood adrenaline (Kety, 1975). The effects are of the nature of an arousal. The phenomenon has been observed in patients with brain injuries (Ingvar and Ciria, 1975) and probably occurs even in comatose states. The increase in CBF in pain and anxiety may be taken as examples of the metabolic regulation of CBF. Any increase in intracranial blood volume will tend to increase the intracranial pressure and mass displacement which can lead to incarceration at the tentorium. Hence it follows that such stimuli may have noxious consequences in comatose patients with intracranial mass-occupying lesions. To avoid pain and anxiety by the liberal use of analgesics even in comatose patients with severe brain injuries has become a routine for some neuroanaesthetists. This principle, already mentioned in the introduction, finds support in the facts discussed here. It is referred to in some detail (and repeatedly) because its

systematic application is not yet generally accepted and implemented. We believe much stands to be gained in terms of survival of critically ill patients by this approach. To take one specific example, for this reason it is contraindicated to use a painful stimulus to assess the level of coma in patients of the types described— suffering from brain trauma, brain tumour, intracerebral haemorrhage, etc. Such painful stimulation will tend to increase CBF, intracranial pressure and to aggravate any tendency to brain incarceration as detected clinically as decerebral rigidity. Autoregulation In the normal brain, CBF is maintained constant despite rather wide variation in cerebral perfusion pressure which is the pressure difference between brain arteries and brain veins. (ICP can be assumed to be almost the same as the pressure in the cerebral veins in practically all conditions.) This mechanism, autoregulation of CBF, has the nature of an active vascular response in that arteriolar constriction results from a perfusion pressure increase and arteriolar dilatation from a pressure decrease. Autoregulation of blood flow occurs in many other tissues, which could suggest that the same mechanism is involved. In both brain and other tissues it has been shown that the autonomic nervous system (perivascular nerves) is not involved (Rapela, Green and Denison, 1967; Eklof et al., 1971; Waltz, Yamaguchi and Regli, 1971). Because the metabolic pattern and level of activity are so different in different tissues, it is not likely that chemical factors (Pco 2 and Po 2 ) are directly involved either. It is most probable then that autoregulation results from myogenic responses of the smooth muscle cells of the arteriolar wall to the stretch caused by the distending transmural pressure. Autoregulation is easily abolished by trauma or other noxious stimuli, in particular following hypoxia. Apparently, the vasodilatation chemically induced by lactic acid can readily override the autoregulatory constrictor response to perfusion pressure increase. Autoregulation can be tested by measuring CBF during induced changes of systemic arterial pressure. We use angiotensin to increase the pressure and trimetaphan in combination with body tilting to decrease the pressure. There is evidence that these two drugs have no direct effect on the cerebral vessels, presumably because they do not readily penetrate the vascular endothelium of the brain vessels, the bloodbrain barrier. Thus, the drugs only influence the tone of the cerebral resistance vessels via their effects on

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metabolic regulation of CBF. Barbiturate intoxication is one such state in which the pattern of depressed function (slowing of e.e.g. and coma), decreased oxygen uptake and reduced CBF conforms to that of the metabolic regulation. The marked decrease of cerebral oxygen uptake and of flow are roughly proportional, reaching values of about 50% of normal in coma levels corresponding to surgical anaesthesia. Why flow decreases in this case is perhaps even more mysterious than why it increases during functional activation, because no known strong vasoconstrictor stimulus is known to accumulate in the brain during barbiturate intoxication. Other drugs produce precisely the same pattern of functional, metabolic and flow depression; a striking example is provided by the steroid i.v. anaesthetic agent, Althesin, studied by McDowall and co-workers (1975). They found a remarkably close time relationship: e.e.g. slowing was almost instantaneous with the arrival of the bolus of the drug to the brain, and cerebrovascular resistance increased less than 4 s later, at a time when no significant washout of carbon dioxide and hence no significant tissue alkalosis could have had time to develop. Thus, just as mentioned in the case of barbiturates, no "explanation" for the reduction of CBF could be offered. Thus the Althesin studies illustrate at the same time the tightness of the coupling between function and metabolism on the one hand and flow on the other—a tightness also in time—and our failure to understand its mechanism.

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Of even greater clinical significance is the displacement to the right of the lower limit of autoregulation of CBF—and of the ischaemia threshold as well. Chronic hypertensives do not tolerate the same low arterial pressure as do normotensives. Induced hypotension. This procedure is fairly widely used in special neuroanaesthetic situations, especially during aneurysm surgery. If the skull is open, then the intracranial pressure is zero, and this may explain the observed tolerance of very low arterial pressures. It is not intended here to review the subject, but merely to stress that hypertensive patients need a higher pressure than normotensives. It should also be noted that, in patients in whom the disease or the surgical intervention has impaired tissue circulation (perhaps a clip has been placed on an artery in order to produce this effect), then hypotension is the most effective means of severely compromising tissue perfusion! A special form of regional induced hypotension is that produced by a vascular surgeon during carotid surgery. During the temporary clamping of the internal carotid artery, which is necessary in order to perform endarterectomy at the carotid bifurcation, the distal arterial "stump" pressure decreases. It has been claimed that during this procedure a stump pressure of 50 mm Hg suffices to assure that the ipsilateral hemisphere is adequately perfused but, in accordance with the above-mentioned facts, hypertensives need a higher pressure than normotensives. This agrees with the recent experience of Sundt and co-workers (1974) in a large series of patients undergoing endarterectomy, in whom the adequacy of hemispheric perfusion during the clamping was measured directly using the xenon-133 i.a. injection method. It would appear more reasonable, therefore, to rely on e.e.g. and on xenon-133 washout to monitor the adequacy of cerebral perfusion during carotid surgery, that is to determine in which cases a temporary bypass shunt must be used. Spontaneous hypovolaemic hypotension. As will be discussed further below, spontaneous hypotension resulting from a reduction in blood volume elicits increased activity of the sympathetic nervous system, including the sympathetic vasoconstrictor fibres to the cerebral vessels. The resultant increase in vessel tone means a displacement to the right of the autoregulatory curve, that is the lower limit of CBF autoregulation as well as the lowest tolerated pressure are both increased. Therefore, in haemorrhagic hypotension, brain ischaemia develops at a higher pressure than during pharmacologically induced hypotension. This is a well-known clinical fact, which might be

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systemic arterial pressure. In the normal brain, the ICP is low and practically uninfluenced by arterial pressure variations, that is variations in systemic arterial pressure can be assumed to produce equal changes in perfusion pressure. However, in patients with increased ICP, variations of this ICP must be taken into account. Autoregulation of CBF also explains the constancy of the CBF normally found upon inducing changes in intracranial pressure. In two experimental studies, such changes produced precisely the same pressureflow relationship as did induced variations in arterial pressure (Haggendal et al., 1970; Symon et al., 1973). In a third study, an increase in CBF at severely increased ICP was found (Symon, 1970). Most probably, this represents a reactive hyperaemia, perhaps caused by a transitory excessive increase in ICP; it was not observed in the two previous studies. Autoregulation has a lower limit, in normotensives at a mean arterial pressure of about 60 mm Hg (fig. 1). Below this limit, CBF decreases and the arteriovenous oxygen difference increases. At an even lower pressure, in normotensives at about 40 mm Hg, symptoms of cerebral ischaemia in the form of hyperventilation, dizziness and "slow cerebration" appear. Autoregulation also has an upper Emit, in normotensives at a mean arterial pressure of about 130 mm Hg. Above this limit the pressure appears to break through the constrictor response. This forced dilatation of the arterioles usually occurs at many discrete sites (multifocally), and is associated with a disruption of the blood-brain barrier and with oedema formation. In our experience in human subjects, however, brief periods of induced hypertension to pressures just beyond the upper limit of autoregulation, while sharply increasing CBF, do not produce any subjective side-effects apart from slight headache and no objective side-effects. In chronic arterial hypertension, the autoregulatory curve is displaced to the right, the cerebral vessels having adapted to the higher pressure by hypertrophy of the vessel wall. Thus chronic hypertensives tolerate a high arterial pressure much better than do normotensives ("break-through point" or upper limit is increased). However, it should be noted that the adaptation of the vessels takes some time. It is well known that in subacute hypertension, as seen in children with glomerulonephritis or in hypertensive toxaemia of pregnancy, arterial pressure values which do not cause symptoms in elderly hypertensives are not tolerated.

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PHYSIOLOGY OF CEREBRAL BLOOD FLOW

Chemical control of CBF (CO2 and O2) Variations in arterial Pco 2 exert a profound influence on CBF (fig. 1). Hypercapnia causes intense cerebral vasodilatation, and hypocapnia causes a indicate a blood flow so low that it compromises tissue constriction so marked that the limit of brain hypoxia oxygenation. With this definition the very low CBF is reached. Around the normal arterial Pco 2 , CBF during severe barbiturate intoxication or deep changes about 4% for each mm Hg change in arterial hypothermia will not be classified as ischaemia Pco 2 . Since the accuracy of the i.a. xenon-133 because the low flow suffices to sustain the low method is of the same order of magnitude, the effects of 1-mm Hg variations in arterial Pco 2 are measurmetabolic rate. In normothermic, lightly anaesthetized man the able. Very accurate arterial Pco 2 determinations critical ischaemic threshold of CBF is about are consequently indispensable for evaluating CBF 20 ml/100 g/min and below this value the e.e.g. data. gradually disappears. At a CBF of about 15 ml/ Carbon dioxide reactivity is mediated by pH 100 g/min, the evoked electrocortical responses variations in cerebrospinal fluid (c.s.f.) around the disappear completely, and at an even lower CBF of arterioles (Elliot and Jasper, 1949; Gotoh, Tazaki and about 6 ml/100 g/min a massive release of K + from Meyer, 1961; Severinghaus et al., 1966;Lassen, 1968; the cells is seen (Astrup et al., 1976). It seems likely Wahl et al., 1970; Pannier et al., 1972). The pH at this that this low value of CBF constitutes that below site depends on the tension of the freely diffusible which cellular death occurs. If this is so, then a carbon dioxide and the local c.s.f. bicarbonate concenpenumbra would seem to exist—CBF between 20 and tration. This dual nature of the chemical control of 6 ml/100 g/min—in which tissue oxygenation is CBF (fig. 2), by arterial Pco 2 and by c.s.f. bicarbonate, inadequate to sustain neuronal function, but is is of importance for understanding the vasoparalysis sufficient for the cells to survive. It is not yet known seen in brain tissue lactic acidosis, as will be discussed how often such a clinical state of presumably revers- later. It is unclear how the pH variations influence ible ischaemic "paralysis" of nerve cells occurs. That the tone of the smooth muscle cells. It is likely that it does exist is well illustrated by the numerous cases the pH inside these cells is the important factor (Wahl of completely reversible focal ischaemic attacks of et al., 1973) and that the effect involves changes in the hemiparesis or hemianopia. concentration of ionized calcium. explained in terms of the autoregulatory curve and its resetting (to the right) by sympathetic nervous stimulation. Ischaemia. Brain tissue ischaemia is here meant to

PERIVASCULAR NERVE ENDING

"ARTERIAL

PCOi

**EXTRACELLULAR HCO3

FIG. 2. Extracellular fluid pH is the main factor controlling cerebral blood flow (CBF) via its influence on the tone of the cerebral arterioles. It is apparently the final common pathway for the chemical control (CO2 and O2) of CBF, the adaptation of CBF, and probably also the metabolic control of CBF.

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pH AROUND AND PRESUMABLY ALSO INSIDE THE SMOOTH MUSCLE CELL IS DETERMINED BY

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compensatory flow changes which keep cerebral venous gas tensions normal. Therefore, no stimulus for chemical control is detectable. The percentage changes in blood viscosity assessed in vivo are approximately equal to those in CBF (Benis, Usami and Chien, 1970; Rosenblum, 1971; Marc-Vergnes et al., 1973). Therefore, changes in diameter of the arterioles might not actually take place. If this is so, then the flow changes are not caused by any alteration in cerebrovascular control but merely by the viscosity changes. This fact does not necessarily mean that viscosity is a limiting factor, for, even in the case of polycythaemia, carbon dioxide inhalation produces a sharp increase of CBF, and in anaemia hyperventilation decreases CBF. CO2 and O 2 in neuroanaesthesia. Only a few comments on this topic need be made. The importance of avoiding anoxia or anoxia combined with hypercapnia (asphyxia) is obvious. Both constitute vasodilator stimuli which, in patients with space-occupying intracranial lesions, may fatally increase ICP and increase mass displacement. A specific example of utmost clinical importance is that of the patient with a head injury in whom adequate ventilation must be assured from the earliest stage. Moderate hypocapnia. The value of inducing cerebral vasoconstriction by hyperventilation during a neurosurgical procedure is well established. Longterm treatment (days or even weeks) with controlled ventilation is used in several clinics. This usually implies a state of moderate hypocapnia but, as a result of the adaptation (normalization) of c.s.f. pH and consequently of CBF to the lower Pco 2 value, this procedure cannot be expected to yield prolonged vasoconstriction. It is likely therefore, as stated by Rossanda and colleagues (1975), that the beneficial effect of this type of intensive care is rather the result of avoidance of any episodes of anoxia or asphyxia, and the ability safely to use effective doses of analgesic and sedative drugs. Severe hypocapnia. There is evidence that at an arterial Pco 2 below 20 mm Hg CBF is so low that the ischaemic threshold for sustaining normal neuronal function (20 ml/100 g/min) is practically reached. This has aroused an intense discussion of whether the beneficial effect of hyperventilation (lower c.s.f. pressure) is not offset by the noxious effect of tissue hypoxia. This topic has been reviewed by Harp and Wollman (1973) who concluded that the evidence for such a noxious effect with even marked hypocapnia (decreased to 10 mm Hg) was not at hand. Nevertheless, because of the scarcity of clinical observations in

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The arterial Pco2-induced flow changes appear to subserve the homeostasis of pH in the brain. With an increase in arterial Pco 2 , flow increases and allows a more efficient washout of metabolically produced carbon dioxide, with the result that the change in tissue Pco 2 (and consequently in tissue pH) is dampened. The converse holds for a decrease in arterial Pco 2 . Of even greater importance to the homeostasis of tissue Pco 2 and pH are the changes in pulmonary ventilation that are caused by carbon dioxide-induced pH changes in c.s.f. at the level of the brainstem. Thus, CBF and ventilation, both of which monitor brain extracellular pH, combine to keep this value rather constant; this system can dampen approximately 95% of a step change in arterial Pco 2 . Adding the buffering capacity and the metabolically induced bicarbonate changes, it must be concluded that brain tissue pH is safeguarded in a truly remarkable way against acute respiratory acidosis and even more against acute respiratory alkalosis. Compensation for chronic changes in arterial Pco 2 is so efficient that c.s.f. pH is almost normal as a result of bicarbonate changes. In this case, CBF is normal, since the adaptation in c.s.f. pH parallels (and causes) CBF adaptation (Severinghaus et al., 1966; Fencl, Vale and Broch, 1969; Pannier and Leusen, 1973). A clinical implication of the slowness of these adaptive processes (they take about 24-36 h) is that a chronically increased Pco 2 should usually not be acutely normalized (Christensen, Brodersen et al., 1973). If it is, the patient will temporarily suffer signs of hypocapnia, including dizziness and somnolence with low CBF. This situation can be avoided by making Pco 2 normal gradually over 1 or 2 days. Moderate changes in the oxygen tension in arterial blood do not influence CBF measurably. Thus, in moderate arterial hypoxia or arterial hyperoxia, the unchanged CBF and the unchanged oxygen uptake mean that tissue Po 2 is not a controlled factor. With a more marked arterial hypoxia, flow increases. This increase appears to be a threshold phenomenon, since a measurable flow increase is not seen until the arterial P o 2 decreases below about 50 mm Hg (McDowall, 1966; Kogure et al., 1970)—the same Po 2 value below which progressive brain tissue lactic acidosis appears (Siesjo and Nielsen, 1971). This finding suggests that in hypoxia CBF is regulated by the periarteriolar pH. If this is correct, then chemical control by carbon dioxide and oxygen are basically the same. Variations in the oxygen-carrying capacity of the blood as seen in anaemia and polycythaemia cause

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PHYSIOLOGY OF CEREBRAL BLOOD FLOW

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various age groups, and especially in patients with intracranial disease, they recommended that for prolonged treatment the arterial Pco 2 should perhaps not be set at less than 25 mm Hg. This must be considered a conservative attitude, but it is reasonable, since at present there are no known therapeutic gains at so low Pco 2 values.

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leagues (1971/72) and by Deshmukh and colleagues (1971/72). Resetting of the autoregulatory curve to the right by sympathetic stimulation (fig. 1.) Recent studies, in part published only in preliminary fashion, allow us to discuss the role of die sympathetic innervation of the brain arteries in a little more detail. Fitch, MacKenzie and Harper (1975) found that during sympathetic stimulation die lower part of die autoreguladon curve Neurogenic control of CBF was altered and diat, at any given arterial pressure, The arteries on the brain surface and even the CBF was less during haemorrhagic hypotension dian larger arterioles inside the brain tissue are supplied by during pharmacologically produced hypotension, an a network of sympathetic and parasympathetic nerve effect diat was traced to die increased sympadietic fibres which run in the same nerve strands (Nielsen, nervous activity during haemorrhagic shock. This Edvinsson and Owman, 1973). The sympathetic shows diat die autoregulatory response to bleeding is fibres stem from the superior cervical ganglion and the less "perfect" dian die response to similar reductions parasympathetic from the facial nerve. of die perfusion pressure following drugs or an The pial arteries respond to topical (local) applica- increased ICP (L. Symon, personal communication). tion of noradrenaline and acetylcholine with constric- The sympadietic nerves tiius counteract die autotion and dilatation respectively (Wahl et al, 1972; regulatory CBF response to a decrease of arterial Kuschinsky and Wahl, 1973). The responses are pressure. Precisely die same is well known from blocked by the corresponding specific antagonists, kidney physiology, where autoregulation cannot be but these antagonists themselves do not influence the seen at all if hypotension is produced by bleeding. vessel diameter when they are applied in the same low This phenomenon, that drug-induced hypotension is concentrations that counteract the agonists. Thus, better "tolerated" tiian haemorrhagic shock, is, under the conditions studied, no evidence of a tonic moreover, well known clinically, and it has been autonomic control over pial arterial tone has been referred to already in die discussion of die clinical adduced. corollaries of autoregulation. A truly colossal experimental effort from numerous What about die upper end of die autoregulatory laboratories has been made to elucidate the physio- curve? Even tiiis curve segment appears to be logical role of the perivascular nerves. Without even displaced to die right by sympadietic stimulation attempting to review this literature and the presumed (Bill, Linder and Linder, 1976). This means diat reasons for the often conflicting results, it shall be acute hypertension is better tolerated if die sympastated that maximal stimulation of the sympathetic dietic nerves are stimulated simultaneously: die nerves reduces CBF by 5-10% (Kobayashi, Waltz and upper limit of die autoregulatory plateau—die breakRhoton, 1971; Aim and Bill, 1973; Meyer and dirough point—is displaced to die right just as in Klassen, 1973) and that a similarly moderate vaso- chronic hypertension. dilator response to parasympathetic stimulation has also The fact diat intense sympadietic stimulation is been shown (Salanga and Waltz, 1973). associated widi spontaneous increases in systemic This shows that the blood flow changes in response arterial pressure makes very good sense indeed. The to maximal neurogenic stimulation are quite small sympadietic nerves, by enhancing arterial and (fig. 1). They correspond to the effect of changes in arteriolar tone during states of arousal, effort, anger arterial Pco 2 of 1-2 mm Hg and cannot, thus, be of etc., enable die brain to tolerate die increased arterial any great importance for regulating CBF. What then pressure witiiout initiating die noxious sequence of can be the functional role of the nervous control of arterial overstretching, blood-brain barrier leakage blood flow to the brain which certainly is much less and fluid extravasation (oedema). intense than in other organs ? Since the nerves supply The effect of die sympadietic nerves on die brain mainly the somewhat larger arteries and arterioles, vessels in acutely enhancing tiieir tonus so diat die it has been suggested that the nerves may be of response curve is reset as in chronic hypertension is in importance for regulating cerebral vascular volume accordance witii die effect of die sympadietic nerves and hence, indirectly, intracranial pressure as on die heart where also a resetting to a new functional suggested independently by Edvinsson and col- level results from such stimulation.

726 CEREBRAL BLOOD FLOW IN SOME DISEASE STATES

Brain tissue acidosis {lactic acidosis)

Brain oedema is often associated with lactic acidosis. The oedema is, in part at least, related to the vasomotor paralysis which tends to increase the capillary hydrostatic pressure. Blood-brain barrier damage is also commonly involved as shown by the radioisotope scanning technique used clinically. The oedema causes distortion of brain tissue and an

increase in intracranial pressure; both these factors tend to induce further tissue hypoxia and hence further tissue lactic acidosis. A most dangerous vicious circle is thus operating. It is therefore important to combat the acidosis by securing adequate oxygenation of the arterial blood and by reducing the arterial Pco 2 . Controlled, moderate hyperventilation by intubation and respirator assistance is now widely used in the intensive therapy of brain-injured patients, in particular patients with traumatic brain injury. Another therapeutic aim is to avoid cerebral vasodilator drugs. To give a specific example, drugs that depress respiration (morphine, pethidine, etc.) are most emphatically contraindicated in a brain-injured patient with spontaneous respiration. This contraindication also holds for volatile anaesthetic agents such as halothane, which can induce a most dangerous triad of hypotension, hypercapnia and cerebral vasodilatation beyond that caused by carbon dioxide. Administration of such drugs is only permissible when ventilation and arterial pressure are controlled. Recognition of these facts is not based on CBF measurements alone. Indeed, ICP measurements have been more important. Yet, it is the combined pressure and flow data that constitute the conceptual basis for the intensive care (including neuroanaesthesia) of the brain-injured patient. CBF in cerebrovascular diseases

In apoplexy (stroke), the patient acutely develops focal neurological symptoms. Arterial pathology, either thromboembolic or haemorrhagic in nature, is usually suspected, but surprisingly often (in about 50% of the cases in many investigations) the arteriographic study obtained by i.a. injection of x-ray contrast material is negative in that no relevant lesions can be seen. CBF studies have contributed to what appears to be the solution of this riddle by demonstrating that even angiographically negative stroke cases have widespread changes in flow: regions with low or high CBF occur and vasomotor responses are abolished (Paulson, Lassen and Skinhej, 1970). This finding supports the theory that lysis of a thromboembolic occlusion often takes place. Two studies of experimental infarction produced by clipping the middle cerebral artery are of particular interest, because the size of the infarct diminished markedly when the animals were hyperventilated (Soloway et al., 1968), but increased when acetazolamide was given (Regli, Yamaguchi and Waltz,

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Even a brief period of inadequate perfusion of brain tissue leads to an intense production of lactic acid. Brain lactic acidosis is a more common and more dangerous disorder than the well-known systemic acidosis such as uraemic acidosis, diabetic ketoacidosis and systemic lactic acidosis. Brain lactic acidosis is marked in patients resuscitated after cardiac arrest. It is present in areas of focal ischaemia resulting from cerebrovascular disease and often develops in severe traumatic brain injury or in cases of brain tumour (Olesen, 1970). In the latter two situations, the ischaemia is presumably caused by severe, often transitory, increases in ICP. Perhaps even the concept of a local increase in brain tissue pressure can be invoked. For example, it would be reasonable to believe that the brain tissue around an acute haematoma is locally under an increased pressure which limits circulation. With the conditions mentioned, brain hypoxia, ischaemic infarction, trauma, tumour, haematoma (which could be called an "acute tumour") the list is still not complete. Brain lactic acidosis is probably also present in severe cases of meningitis and subarachnoid bleeding, and it reaches extreme degrees in so-called brain death. It is on this basis that brain tissue lactic acidosis claims far more clinical importance than does classical systemic acidosis. Brain tissue acidosis is characterized by a state of cerebral vasomotor paralysis, particularly abolition of CBF autoregulation. This socalled luxury perfusion syndrome (Lassen, 1966) is a pathophysiological consequence of chemical control: the local acidosis causes a dilatation of the brain arteries. The blood flow sometimes exceeds the normal flow but more often the hyperaemia is only relative, that is in excess of local metabolic demands. Paradoxical flow responses frequently occur as when strong vasodilator stimuli such as carbon dioxide or papaverine lead to a flow decrease {intracerebral steal) or vasoconstrictor stimuli such as hypocapnia or aminophylline cause a flow increase in acidotic brain tissue (inverse intracerebral steal). Variations in intracranial pressure appear to underlie many of these paradoxical reactions.

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1971). In the normal brain, hypocapnia resulting from hyperventilation reduces CBF, and carbonic anhydrase inhibition caused by acetazolamide increases CBF. In the vasoparalytic focal area, the flow changes go in the opposite direction (paradoxical reactions). Christensen, Paulson and colleagues (1973) have recently tried to employ hyperventilation as a treatment in a series of patients with apoplexy, but no convincing clinical improvement was seen. A likely explanation is that the treatment was not started until some hours after the onset of symptoms. Many people, lay as well as medical, think that common senile or presenile atrophic brain disease (senile dementia or just senility) is caused by cerebrovascular disease in the form of a chronic, relentlessly stenosing arteriosclerotic process. Dementia in the old is often simply called "cerebral arteriosclerosis", a term expressing this thought. However, this thought is erroneous, for there is no relationship between the location of the pathological changes in the brain and the vascular anatomy. Patients with senile dementia have a reduced CBF, but it is only reduced in proportion to the decrease in cerebral oxygen uptake, that is the blood supply relative to demand is normal (Lassen, Feinberg and Lane, 1960). The control of cerebral circulation including its autoregulation is normal in sharp contrast to what would be predicted by the chronic, progressive-stenosis concept (Simard et al., 1971).

walls and outfiltration of oedema fluids, not to vascular spasms as often assumed previously (Lassen and Agnoli, 1972).

CBF in arterial hypertension Many years ago it was established that subjects with arterial hypertension but without brain symptoms have a perfectly normal CBF (Lassen, 1959). In other words, the cerebrovascular resistance is increased in proportion to the increase in pressure. As already mentioned, an autoregulation of CBF is preserved, but it is reset at a higher pressure. The observations made during induced hypertension are of particular interest. In normotensive and hypertensive individuals, an upper limit of autoregulation of CBF has been found beyond which CBF suddenly increases (Skinhoj and Strandgaard, 1973; Strandgaard et al., 1973), this upper limit being displaced towards higher pressure values in hypertensive individuals. A decrease in flow was not seen in any single patient. These findings suggest that the cerebral symptoms characteristic of malignant hypertension (hypertensive encephalopathy) are related to this so-called breakthrough of autoregulation, that is the symptoms are caused by overdistension of vessel 6i

CBF in epileptic seizures The marked flow increase in the brain during seizure activity has long been recognized. In spontaneously breathing animals and man, a temporary asphyxia supervenes. But CBF increases by about 100% even if normoxia and normocapnia are maintained throughout by artificial ventilation combined with curarization (Plum, Posner and Troy, 1968; Brodersen et al., 1973). The mechanism of the flow increase has recently been debated. In spontaneously breathing animals, a pronounced brain tissue lactic acidosis develops during the seizures (Gurdjian, Webster and Stone, 1947; Klein and Olsen, 1947; King et al., 1967). In animals kept normoxic and normocapnic, it is more difficult to demonstrate the acidosis (Plum, Posner and Troy, 1968; Beresford, Posner and Plum, 1969; Collins, Posner and Plum, 1970). Now this problem has been solved: animal experiments involving very rapid freezing of the brain tissue show about a sixfold increase in tissue lactate (from 1.1 to 6.7 mmol/litre) after only 5 s of seizure activity (Bolwig and Quistorff, 1973). Supportive evidence is available from the observation of a temporary increase in the respiratory quotient of the brain (from just below 1.0 to about 1.3) during induced seizures (Plum, Posner and Troy, 1968; Brodersen et al., 1973). The simultaneous increase in cerebral venous Po 2 indicates that tissue hypoxia probably is not involved in producing the lactic acidosis. Perhaps the accelerated utilization and production of adenosine triphosphate (ATP) change the balance between the initial (glycolytic) and the final (oxidative) breakdown of glucose without oxygen lack being involved. Secondary factors might, however, also play a role. The autoregulation of CBF is not upheld during seizures (Plum, Posner and Troy, 1968; Brennan and Plum, 1971) presumably because of the acidosis. The increase in arterial pressure during seizure will therefore contribute to the increase in CBF. Other flow-increasing factors such as an increase in brain extracellular fluid potassium concentration or osmolality could also be involved. GENERAL OUTLINE OF PHARMACOLOGY OF CEREBRAL BLOOD FLOW

Even a brief discussion of drug effects on CBF would necessitate the reviewing of a great number of studies

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728 involving many different methodological approaches. Furthermore, because most of the studies concern effects in normal animals or normal man, it would be difficult to illustrate adequately that cerebral circulatory responses to drugs are often totally different in brain diseases. This fact was stressed in the section on brain tissue acidosis where the paradoxical CBF changes—steal or inverse steal—were presented. This fact is important for the clinical application of CBF data, since it is in such states that flow changes really matter. With this consideration in mind, a summary of drug effects on CBF in the normal brain will be given.

Cerebral vasodilators The list of vasodilators comprises acetazolamide, papaverine, volatile anaesthetic agents and drugs that cause high arterial Pco 2 or hyperosmolality (Sokoloff, 1959; Alexander and Lassen, 1970). To this list must also be added the drugs that appear to increase brain flow secondary to enhancement of neuronal function: analeptic drugs, ketamine, nicotine and adrenaline belong to this group. Cerebral vasoconstrictors A direct vasoconstrictor action is found with drugs that cause reduced arterial Pco 2 , or hypo-osmolality, and with xanthine derivatives such as theophylline (a component of many pharmaceutical preparations, for example aminophylline, Euphyllin, Cordalin and xanthinol nicotinate) (Gottstein and Paulson, 1972). Drugs that depress cerebral function also tend to decrease CBF (if an independent vasodilator effect is absent): the barbiturates belong to this group. Hypothermia also causes vasoconstriction.

PHARMACOLOGICAL EFFECTS OF SPECIFIC ANAESTHETIC DRUGS ON CEREBRAL BLOOD FLOW

Until recently, general anaesthetic agents were considered to produce unconsciousness and analgesia by depressing cerebral functional activity, metabolism and blood flow. Barbiturates have this effect and were taken to represent all anaesthetic drugs. However, recent studies have completely changed this simplistic concept, and excitation in some brain regions by some drugs has been shown by many authors. A notable example is that of ketamine, where many structures show enhanced electrical activity producing an unresponsive state resembling catalepsia. Here also it seems that the CBF change (an increase) is related, directionally at least, to that of brain metabolism (an increase). With regard to effect on CBF, anaesthetic drugs may be classified as follows: all gaseous anaesthetic agents, even nitrous oxide, are cerebral vasodilators; the i.v. anaesthetic drugs are cerebral vasoconstrictors, ketamine constituting the only exception so far known. Volatile and gaseous agents Halothane has repeatedly been shown to be a cerebral vasodilator. In clinical studies with 1.2% halothane in oxygen, normocapnia and hypotension, Wollman and colleagues (1964) found CBF increase of 14% associated with decrease of 9% in the cerebral metabolic rate of oxygen (CMRo2), whereas Christensen, Hoedt-Rasmussen and Lassen (1967), with 1.0% halothane in oxygen, normocapnia and a maintained arterial pressure, found CBF increase of 27% and CMRo 2 decrease of 26% in young men. Experimental studies by Smith (1973) showed a good correlation of CMRo 2 and cerebral arterio-venous oxygen difference with depth of halothane anaesthesia. Studies with halothane, given to patients with moderate intracranial hypertension, always showed a further increase of ICP, which might occur quite suddenly, leading to local compressions resulting from brain shift (Fitch and McDowall, 1971). Under clinical conditions, these marked ICP increases are transient (10-30 min), and may be minimized, or even abolished, by prior induction of hypocapnia (10 min) in the majority of, but not in all, cases (Adams et al., 1972; Misfeldt, Jorgensen and Rishoj, 1974). The recovery from a hypocapnic halothane anaesthesia deserves special attention to adequacy of ventilation (Jorgensen and Misfeldt, 1975). Methoxyflurane resembles halothane in its cerebral metabolic effects (dose-dependent CMRo 2 decrease),

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Drugs with no effect on CBF Many substances, such as noradrenaline, angiotensin or trimetaphane, that influence vascular tone markedly in other organs are without direct influence on CBF even if they are infused directly into the internal carotid artery (Olesen 1972, 1973). These drugs influence CBF only secondarily, that is as a result of their effect on systemic arterial pressure. However, adrenaline appears to increase CBF (Sokoloff, 1959), but this effect is probably a flow response secondary to anxiety and arousal, not a direct vasomotor response. Alpha-receptor blocking agents such as phenoxybenzamine, phentolamine or Hydergine are without influence on CBF (Hoff et al., 1972; Olesen and Skinhoj, 1972; Skinhoj, 1972).

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spontaneous respiration. Thus, during spontaneous respiration, an additional cerebral vasodilatation will be provoked by these anaesthetic agents. Barbiturates Pierce and colleagues (1962) demonstrated thiopentone to be a pronounced, and dose-dependent, cerebral vasoconstrictor in man. During normocapnia, deep thiopentone anaesthesia causes a parallel reduction of about 50% of CMRo 2 and CBF, the last mentioned being further reduced when hypocapnic vasoconstriction is added. Interpretation of cerebral metabolic depression induced by thiopentone may be difficult, as experimental studies have disclosed an acute tolerance to thiopentone (Altenburg, Michenfelder and Theye, 1969). The degree of CMRo 2 decrease, following continuous administration of thiopentone, is reduced if pretreatment with thiopentone is given, despite concomitant higher concentrations in blood and c.s.f. Nevertheless, continuous administration of thiopentone has been successfully employed for neurosurgical procedures, using, on average, a total of 1230 mg (Hunter, 1972). The same dose-dependent and parallel reductions of CBF and CMRo 2 following phenobarbitone have been demonstrated experimentally (Nilsson and Siesjo, 1975). The mechanism by which barbiturates influence the brain is still a matter of discussion. It has been claimed that the cerebral metabolic effects of thiopentone are secondary to the functional effects (perhaps on synapses) contrary to the effect of hypothermia that influence cellular enzymes directly (Michenfelder, 1974). Thiopentone affords some cerebral protection in hypoxia because of the diminished energy requirements associated with the reduced cerebral function. In keeping with this, an energy failure (reduction of ATP) related to the marked CMRo 2 reduction induced by thiopentone could not be demonstrated experimentally (Carlsson, Harp and Siesjo, 1975). On the contrary, as an outstanding effect of all barbiturates, a shift in favour of an oxidated (high energy) state, a lowering of lactate, and thus an increased intracellular pH has been disclosed (Nilsson and Busto, 1973). Smith and colleagues (1974) believe that the marked barbiturate protection in experimental focal cerebral ischaemia is primarily related to decreased CBF in healthy brain areas and a related reduction of ICP. The non-barbituric induction agent, propanidid has been found to be a potent and short-acting cerebral metabolic depressant associated with a CBF

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and also increases CBF (Michenfelder and Theye, 1973). Administration of 1.5% methoxyflurane to patients with space-occupying lesions induces an ICP increase which could not be completely counteracted by moderate hyperventilation (Fitch et al., 1969b). Isoflurane and enflurane both cause a significant cerebral metabolic depression associated with cerebral vasodilatation in dogs (Cucchiara, Theye and Michenfelder, 1974; Michenfelder and Cucchiara, 1974). During enflurane anaesthesia and induced hypocapnia seizure activity was sometimes elicited associated with increase of CMRo 2 . Nitrous oxide, administered in a concentration of 70% in man, causes a decrease in CMRo 2 of about 25% without significantly affecting the CBF during normocapnia (Wollman et al., 1965). Besides the unaffected CBF, Smith and co-workers (1970) demonstrated that the cerebral autoregulation is well preserved during nitrous oxide anaesthesia in man. The unchanged CBF in face of a reduced CMRo 2 may be considered a state of relative increase in flow. In agreement with this concept Henriksen and Jergensen (1973) found ICP increases associated with 66% nitrous oxide administration in patients with intracranial disorders, and concluded that nitrous oxide was a significant cerebral vasodilator. When evaluating the effects of nitrous oxide, the previously mentioned arousal reactions (increase in CBF and ICP) associated with painful stimuli and anxiety in patients subjected to incomplete anaesthesia should be recalled. The excitation phase during nitrous oxide induction represents a phenomenon influencing CBF and ICP in the same manner (Brodersen, 1975). Cyclopropane used clinically, in concentrations ranging from 5% to 37%, causes a depression of CMRo 2 , without correlation with the depth of anaesthesia (Alexander et al., 1970). Furthermore, an increased cerebral lactate production was found following 5% cyclopropane. Twenty per cent cyclopropane increases the CBF by about 50% during normocapnia in man (Smith et al., 1970). These rather unusual and variable cerebral effects of increasing concentrations of cyclopropane have been found experimentally to be secondary to an increase in the concentration of circulating catecholamines associated with this anaesthetic agent (Michenfelder and Theye, 1972). All the above-mentioned anaesthetic agents reduce the ventilatory carbon dioxide response, and consequently arterial Pco 2 will be increased during

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decrease in dogs (Takeshita, Miyauchi and Ishikawa, 1973).

CONCLUDING CLINICAL COMMENTS RELATING TO

Ketamine Clinical studies have proved ketamine to be a pronounced cerebral vasodilator, as it increases CBF by 62%, with an increase in CMRo 2 of 12% during normocapnia (Takeshita, Okuda and Sari, 1972). The vasodilatation is so pronounced in normal man that a marked ICP increase results (Gardner, Olson and Lichtiger, 1971). Although ketamine has anaesthetic properties, it has been shown to be a cerebral stimulant which is able to induce seizure activity in epileptics (Bennett et al., 1973). Hougaard, Hansen and

NEUROANAESTHESIA

As repeatedly pointed out, we can influence the CBF and CMRo 2 in several ways dependent on the choice of anaesthetic drugs and technique. We may therefore ask, what level of CBF is the most appropriate during neuroanaesthesia ? Induction of cerebral hyperaemia in a patient with a brain lesion should always be avoided, as it increases the ICP and causes a cerebral "steal". Consequently, cerebral vasodilators, for example inhalation anaesthetic agents and hypercapnia, are contraindicated. In

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Brodersen (1974) have suggested that ketamine is not a direct cerebrovasodilator, but that it might affect regional blood flow secondary to drug-induced Narcotic analgesics and neuroleptic drugs changes in regional neuronal activity. Incremental doses of morphine cause progressive and Ketamine has repeatedly been shown to provoke parallel decreases of CMRo 2 and CBF of about 15% substantial increases of ICP in patients with intrain dogs with maintained normocapnia (Takeshita, cranial pathology (Gibbs, 1972; Shapiro, Wyte and Michenfelder and Theye, 1972). This effect could be Harris, 1972). This increase might be reversed with reversed by n-allynormorphine. However, when n- thiopentone given after the administration of ketamine allynormorphine was given alone it had cerebral (Wyte et al., 1972). effects similar to, but less pronounced than morphine. Pethidine causes a CMRo 2 reduction of the Althesin same order as morphine (Messick and Theye, 1969). Althesin is a steroid compound with short-lasting Although morphine per se is a cerebral vaso- anaesthetic properties. Experimentally it has been constrictor, this effect will be completely abolished found to cause a marked CMRo 2 reduction and a by hypercapnic vasodilatation. It has recently been concomitant clear-cut vasoconstriction (Pickerodt et demonstrated during normocapnia that morphine- al., 1972). A further increase of the dose will cause a nitrous oxide anaesthesia does not significantly affect further CBF decrease, but simultaneously a marked CBF or cerebral autoregulation in normal man hypotension will be induced. In normal man the (Jobes et al., 1975). short-lasting vasoconstriction is so pronounced that a Fentanyl has been shown in normal man not to marked ICP reduction has been demonstrated during influence either CBF or CMRo 2 significantly under normocapnia (Takahashi et al., 1973). Althesin has normocapnia (Sari, Okuda and Takeshita, 1972). also been found to be a valuable drug in the presence In dogs, fentanyl causes a marked and short-lasting of intracranial hypertension (Turner et al., 1973). decrease of both CBF and CMRo 2 , whereas droperidol was found to be a more potent and long-acting Curare cerebral vasoconstrictor, which does not influence Previously it has been claimed that i.v. adminiCMRo 2 (Michenfelder and Theye, 1971). For the stration of tubocurarine was without any influence on purpose of a neuroleptanaesthesia, a combination of the brain. In neurosurgical patients with normal ICP, fentanyl and droperidol is administered. In animal Tarkkanen, Laitinen and Johansson (1974) found a studies, this combination causes a long-lasting CBF significant ICP increase associated with curare decrease, combined with an initial CMRo 2 reduction. medication during maintained normocapnia. They A significant ICP decrease in patients with normal suggested from their data that the pressure increase c.s.f. pathways as well as with intracranial space- was caused by increased pulsatile blood flow in the occupying lesions will be associated with neuro- brain, associated with histamine release. If so, leptanaesthesia (Fitch et al., 1969a). pancuronium might be preferable as a relaxant drug. The benzodiazepine derivative diazepam has Another explanation of the ICP increase would be an recently been shown to cause a parallel depression of arousal effect during incomplete anaesthesia, and in both CMRo 2 and CBF in comatose patients with this case the type of muscle relaxant is immaterial. diffuse brain damage (Cotev and Shalit, 1975).

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Astrup, J., Symon, L., Branston, N., and Lassen, N. A. (1976). Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischaemia. Stroke (in press). Benis, A. M., Usami, S., and Chien, S. (1970). Effect of hematocrit and inertial losses on pressure-flow relations in the isolated hindpaw of the dog. Circ. Res., 27, 1047. Bennett, D. R., Madsen, J. A., Jordan, W. S., and Wiser, W. C. (1973). Ketamine anesthesia in brain-damaged epileptics: electroencephalographic and clinical observations. Neurology (Minneap.), 23, 449. Beresford, H. R., Posner, J. B., and Plum, F. (1969). Changes in brain lactate during induced cerebral seizures. Arch. Neurol., 20, 243. Bill, A., Linder, J., and Linder, M. (1976). Sympathetic effect on cerebral blood vessels in acute arterial hypertension. Acta Physiol. Scand., 96, 27A. Bolwig, T. G., and Quistorff, B. (1973). In vivo concentration of lactate in the brain of conscious rats before and during seizures: new ultra-rapid technique for the freezesampling of brain tissue. J. Neurochem., 21, 1345. Brennan, R. W., and Plum, F. (,1971). Dissociation of autoregulation and chemical regulation in cerebral circulation following seizures; in Brain and Blood Flow (ed. R. W. R. Russell), p. 218. London: Pitman. Brodersen, P. (1975). Discussion on psychoactive drugs and anxiety, their influence on cerebral circulation and metabolism; in Brain Work: The Coupling of Function, Metabolism and Blood Flow in the Brain (eds D. H. Ingvar and N. A. Lassen), p. 464. Copenhagen: Munksgaard. Paulson, O. B., Bolwig, T. G., Rogon, Z. E., Rafaelsen, O. J., and Lassen, N. A. (1973). Cerebral hyperemia in electrically induced epileptic seizures. Arch. Neurol., 28, 334. Carlsson, C , Harp, J. R., and Siesjo, B. K. (1975). Metabolic changes in the cerebral cortex of the rat induced by intravenous pentothal sodium. Acta Anaesthesiol. Scand., 57,7. Christensen, M. S., Brodersen, P., Olesen, J., and Paulson, O. B. (1973). Cerebral apoplexy (stroke) treated with or without prolonged, artificial hyperventilation. I I : Cerebrospinal fluid acid-base balance and intracranial pressure. Stroke, 4, 620. REFERENCES Hoedt-Rasmussen, K., and Lassen, N. A. (1967). Adams, F. W., Gronert, G. A., Sundt, T. M., and Cerebral vasodilatation by halothane anaesthesia in man Michenfelder, J. D. (1972). Halothane, hypocapnia, and and its potentiation by hypotension and hypercapnia. cerebrospinal fluid pressure in neurosurgery. AnesBr.J. Anaesth., 39, 927. thesiology, 37, 510. Paulson, O. B., Olesen, J., Alexander, S. C , Skinhoj, Alexander, S. C , Colton, E. T., Smith, A. L., and Wollman, E., Dam, W. H., and Lassen, N. A. (1973). Cerebral H. (1970). The effects of cyclopropane on cerebral and apoplexy (stroke) treated with or without prolonged, systemic carbohydrate metabolism. 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According to the pathophysiology of focal brain lesions, induction of vasoconstriction in the normal parts of the brain will decrease the ICP and thus improve the perfusion of the lesions ("inverse steal"). The anaesthetic agents chosen should therefore be potent depressors of cerebral metabolism, preferably with an associated vasoconstrictor effect. The anaesthetic technique should include moderate hypocapnia, that is passive hyperventilation. Among the drugs available today, the barbiturates are the most suitable since they produce proportionate reductions in function, metabolism and flow. Other relevant alternatives are neuroleptanaesthesia and Althesin. During anaesthesia, it is important to avoid marked arterial hypotension because of the defective autoregulation. However, there are also arguments in favour of moderate hypotension, because this will tend to reduce oedema production in damaged regions with vasodilatation ("luxury perfusion").

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