Br.J. Anaesth.
(1976), 48, 719
PHYSIOLOGY OF CEREBRAL BLOOD FLOW
N. A. LASSEN AND M.
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 appro-
priate 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 space-
occupying 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 para-
doxical 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 vaso-
constrictor 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
NIELS A. LASSEN, M.D.; M. STIG CHRISTENSEN, M.D.;
Department of Clinical Physiology, Bispebjerg Hospital,
DK-2400 Copenhagen NV, and Department of Anaes-
thesiology, Copenhagen Municipal Hospital at Hvidovre,
DK-2650 Hvidovre, Denmark.
Correspondence to M. S. C. at Copenhagen Municipal
Hospital.
S. CHRISTENSEN
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 neuro-
anaesthetists, 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 (hemi-
spheric) metabolism to be performed. Lassen and
Munck (1955) modified the classical Kety-Schmidt
technique by substituting the inhalation of a radio-
active inert gas (krypton-85) in place of nitrous oxide.
By injection of fluid containing dissolved krypton-
85 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 measure-
ment 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
720
linear correlation to the value found by stochastic
analysis of the curve from the first 10 min clearance.
Despite the apparent differences between the Kety-
Schmidt inert gas inhalation method and the Lassen-
Ingvar 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 contri-
buted little to the development of the concepts that
relate to clinical problems which the present paper
aims at clarifying.
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 opera-
ting 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,
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 exam-
ple in skeletal muscle, where local hyperaemia is
found following local contractions and local metabolic
stimulation.
In disease states, the principle of metabolic regula-
tion of CBF is also well established. The enhanced
function, oxygen uptake and bloodflowduring epilep-
tic 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)
nerve cellll activity
tt <
pertusion pres
CHEMICAL NEUROGENIC
I level of activity of svmpat f c
Drain LCr pH 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 main-
tained 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 funda-
mental 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
PHYSIOLOGY OF CEREBRAL BLOOD FLOW
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 pre-
cisely 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 resis-
tance 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.
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 dis-
placement 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 introduc-
tion, finds support in the facts discussed here. It is
referred to in some detail (and repeatedly) because its
721
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, intra-
cerebral 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 (peri-
vascular 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 trime-
taphan in combination with body tilting to decrease
the pressure. There is evidence that these two drugs
have no direct effect on the cerebral vessels, pre-
sumably because they do not readily penetrate the
vascular endothelium of the brain vessels, the blood-
brain barrier. Thus, the drugs only influence the tone
of the cerebral resistance vessels via their effects on
722
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 pressure-
flow 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 normo-
tensives 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 hyper-
ventilation, dizziness and "slow cerebration" appear.
Autoregulation also has an upper Emit, in normoten-
sives 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 subjec-
tive 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.
BRITISH JOURNAL OF ANAESTHESIA
Of even greater clinical significance is the displace-
ment 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 hypoten-
sion is the most effective means of severely compro-
mising 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 clamp-
ing 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 auto-
regulatory curve, that is the lower limit of CBF auto-
regulation as well as the lowest tolerated pressure are
both increased. Therefore, in haemorrhagic hypoten-
sion, brain ischaemia develops at a higher pressure
than during pharmacologically induced hypotension.
This is a well-known clinical fact, which might be
PHYSIOLOGY OF CEREBRAL BLOOD FLOW 723

explained in terms of the autoregulatory curve and its Chemical control of CBF (CO2 and O2)
resetting (to the right) by sympathetic nervous Variations in arterial Pco 2 exert a profound
stimulation. influence on CBF (fig. 1). Hypercapnia causes intense
Ischaemia. Brain tissue ischaemia is here meant to 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
metabolic rate. of 1-mm Hg variations in arterial Pco 2 are measur-
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 concen-
penumbra 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.

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

PERIVASCULAR "ARTERIAL PCOi

NERVE ENDING **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.
724
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 remarka-
ble 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 normal-
ized (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
BRITISH JOURNAL OF ANAESTHESIA
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 approxi-
mately 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 hyperventi-
lation 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 hyper-
capnia (asphyxia) is obvious. Both constitute vaso-
dilator 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. Long-
term 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. Neverthe-
less, because of the scarcity of clinical observations in
PHYSIOLOGY OF CEREBRAL BLOOD FLOW 725

various age groups, and especially in patients with leagues (1971/72) and by Deshmukh and colleagues
intracranial disease, they recommended that for pro- (1971/72).
longed treatment the arterial Pco 2 should perhaps not Resetting of the autoregulatory curve to the right by
be set at less than 25 mm Hg. This must be considered sympathetic stimulation (fig. 1.) Recent studies, in part
a conservative attitude, but it is reasonable, since at published only in preliminary fashion, allow us to
present there are no known therapeutic gains at so discuss the role of die sympathetic innervation of the
low Pco 2 values. brain arteries in a little more detail. Fitch, MacKenzie
and Harper (1975) found that during sympathetic
Neurogenic control of CBF stimulation die lower part of die autoreguladon curve
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 auto-
tion 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 sympa-
stated 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 break-
Rhoton, 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)
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 resusci-
tated 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 so-
called 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.
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
BRITISH JOURNAL OF ANAESTHESIA
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 respi-
rator 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 contra-
indication also holds for volatile anaesthetic agents
such as halothane, which can induce a most danger-
ous 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 neuroanaes-
thesia) 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 arterio-
graphic 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 wide-
spread 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 acetazola-
mide was given (Regli, Yamaguchi and Waltz,
PHYSIOLOGY OF CEREBRAL BLOOD FLOW
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 (paradoxi-
cal reactions). Christensen, Paulson and colleagues
(1973) have recently tried to employ hyperventila-
tion 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 cerebro-
vascular 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 propor-
tion 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).
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 hyperten-
sion are of particular interest. In normotensive and
hypertensive individuals, an upper limit of auto-
regulation 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 hyperten-
sive individuals. A decrease in flow was not seen in
any single patient. These findings suggest that the
cerebral symptoms characteristic of malignant hyper-
tension (hypertensive encephalopathy) are related to
this so-called breakthrough of autoregulation, that is
the symptoms are caused by overdistension of vessel
6i
727
walls and outfiltration of oedema fluids, not to
vascular spasms as often assumed previously (Lassen
and Agnoli, 1972).
CBF in epileptic seizures
The marked flow increase in the brain during
seizure activity has long been recognized. In spon-
taneously 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 com-
bined 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 osmola-
lity 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
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 circu-
latory 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.
Drugs with no effect on CBF
Many substances, such as noradrenaline, angio-
tensin 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).
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.
BRITISH JOURNAL OF ANAESTHESIA
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 un-
responsive 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 Christen-
sen, 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 differ-
ence 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),
PHYSIOLOGY OF CEREBRAL BLOOD FLOW
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 Michen-
felder, 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 conse-
quently arterial Pco 2 will be increased during
729
spontaneous respiration. Thus, during spontaneous
respiration, an additional cerebral vasodilatation will
be provoked by these anaesthetic agents.
Barbiturates
Pierce and colleagues (1962) demonstrated thio-
pentone 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, Michen-
felder and Theye, 1969). The degree of CMRo 2
decrease, following continuous administration of
thiopentone, is reduced if pretreatment with thio-
pentone is given, despite concomitant higher con-
centrations 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 thio-
pentone 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 out-
standing 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
730 BRITISH JOURNAL OF ANAESTHESIA

decrease in dogs (Takeshita, Miyauchi and Ishikawa, Brodersen (1974) have suggested that ketamine is not
1973). 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 intra-
in 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 mor-
phine. 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. admini-
CMRo 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).
CONCLUDING CLINICAL COMMENTS RELATING TO
Ketamine NEUROANAESTHESIA

Clinical studies have proved ketamine to be a pro-
nounced 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 stimu-
lant which is able to induce seizure activity in epilep-
tics (Bennett et al., 1973). Hougaard, Hansen and
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 anaesthe-
tic agents and hypercapnia, are contraindicated. In
PHYSIOLOGY OF CEREBRAL BLOOD FLOW
this context it has to be emphasized that the arousal
effect associated with pain and anxiety during an
incomplete anaesthesia might induce cerebral vaso-
dilatation and thus hyperaemia. Because of the loss of
autoregulation an increased arterial pressure might be
deleterious as it induces hyperaemia and oedema in
the brain.
The main problem will often be, how to improve
the tolerance to partial ischaemia in a damaged brain.
Some degree of protection might be obtained by deep
barbiturate anaesthesia, but, as has been pointed out
previously, the decreased oxygen uptake during
anaesthesia probably represents only the metabolic
consequence of reduced cortical function and does not
represent any diminution of the oxygen requirements
to maintain basic brain cell viability.
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 hypo-
capnia, 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 auto-
regulation. 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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