raised intracranial and cerebral blood flowjnnp.bmj.com/content/jnnp/36/2/161.full.pdf · and...

Journal of Neurology, Neurosurgery, and Psychiatry, 1973, 36, 161-170

Raised intracranial pressure and cerebral blood flow2. Supratentorial and infratentorial mass lesions in primates

I. H. JOHNSTON, J. 0. ROWAN, A. M. HARPER, AND W. B. JENNETT

From the Medical Research Council Cerebral Circulation Research Group at the Instituteof Neurological Sciences, Glasgow, and the Wellcome Surgical Research Institute,

University of Glasgow

SUMMARY Changes in cerebral blood flow with increasing intracranial pressure were studied inanaesthetized baboons during expansion of a subdural balloon in one of two different sites. With aninfratentorial balloon, cerebral blood flow bore no clear relation to intracranial pressure, but waslinearly related to cerebral perfusion pressure. Apart from an initial change in some animals,cerebrovascular resistance remained constant with increasing intracranial pressure, and auto-regulation appeared to be lost from the outset. With a supratentorial balloon, cerebral blood flowremained constant as intracranial pressure was increased to levels around 60 mmHg, correspondingto a cerebral perfusion pressure range of approximately 100 to 40 mmHg. Cerebrovascular resistancefell progressively, and autoregulation appeared to be effective during this phase. At higher intra-cranial pressure levels (lower cerebral perfusion pressure levels), autoregulation was lost and cerebralblood flow became directly dependent on cerebral perfusion pressure. The importance of the causeof the increase in intracranial pressure on the response of the cerebral circulation and the relevanceof these findings to the clinical situation are discussed.

In a previous study the effect of raised intra-cranial pressure on cerebral blood flow wasexamined during infusion of fluid into thecisterna magna of anaesthetized baboons (John-ston, Rowan, Harper, and Jennett, 1972a).Three sequential phases were observed; aninitial phase in which cerebral blood flow re-mained relatively constant (intracranial pressure0-50 mmHg), a phase of hyperaemia (intra-cranial pressure 50-85 mmHg), and finally aphase in which cerebral blood flow fell pro-gressively with further increase of intracranialpressure (intracranial pressure >85 mmg Hg).These observations differ from previous reportsand add to the already considerable variation inboth clinical and experimental findings on theeffects of raised intracranial pressure on cerebralblood flow (Kety, Shenkin, and Schmidt, 1948;Greenfield and Tindall, 1965; Langfitt, Kassell,and Weinstein, 1965; Zwetnow, 1970; Lowelland Bloor, 1971). The clinician, measuring intra-cranial pressure or even cerebral perfusionpressure, lacks, therefore, a secure basis from

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which to draw quantitative conclusions aboutcerebral blood flow in states of intracranialhypertension.The response of the cerebral circulation to

raised intracranial pressure will depend, ingeneral terms, on changes in perfusion pressureand vascular resistance. Such changes will them-selves be influenced by factors such as the causeand time course of the increase in intracranialpressure. It is therefore unrealistic to attempt todefine a single type of quantitative relationshipbetween either intracranial pressure or cerebralperfusion pressure and cerebral blood flow.Attention should be directed to the differentpatterns of response of the cerebral circulationwhich may be evoked by different forms ofintracranial hypertension.The aim of the present study has been to

examine changes in cerebral blood flow occur-ring during increased intracranial pressure dueto a focal mass in either the supratentorial orthe infratentorial subdural space. The effect ofthe site of the lesion on the response of the

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cerebral circulation has been interpreted interms of changes in cerebral perfusion pressure,cerebrovascular resistance and autoregulatoryfunction.

METHODS

Baboons weighing between 9-5 and 12 5 kg wereused. Anaesthesia was induced with phencyclidinehydrochloride (10 mg) and thiopentone sodium(60 mg), and maintained with phencyclidine hydro-chloride, suxamethonium chloride, and nitrousoxide/oxygen mixture. Controlled ventilation wascontinued throughout using a Starling pump deliver-ing a tidal volume between 150 and 250 ml., adjustedto maintain an arterial pCO2 of approximately40 mmHg. A continuous slow intravenous infusionof 0-90 saline was given during each experiment.The following parameters were measured.

INTRACRANIAL PRESSURE This was measured con-tinuously from a polyethylene cannula inserted intothe right lateral ventricle via a twist drill hole 1 cmlateral to the bregma. In the majority of animalscerebrospinal fluid pressure was also recorded fromeither the cisterna magna or the lumbar subarachnoidspace via a polyethylene cannula inserted under directvision. Pressures were measured using strain gaugetransducers (Bell and Howell), calibrated against amercury column and recorded on standard two-channel paper chart recorders (Devices).

CEREBRAL BLOOD FLOW Two methods were used:(1) a series of 133Xenon clearance curves were ob-tained at approximately 30 minute intervals. A sluginjection of 0 5 mCi133 Xenon, dissolved in 0A45 to0 55 ml. saline at constant temperature, was givenvia a polyethylene cannula in the proximal stump ofthe right lingual artery (the external carotid arteryhaving been ligated). The rate of clearance of gammaactivity was measured using a collimated I in. sodiumiodide crystal detector placed over the right parietalregion. Cerebral blood flow was calculated from theinitial slope and by the height over area techniqueusing the 10 minute correction. (2) An electro-magnetic flow probe (Nycotron) was placed on theexposed right common carotid artery after ligationof the external carotid artery.

OTHER PARAMETERS Systemic arterial pressure wasmeasured using a polyethylene catheter placed in theabdominal aorta via the left femoral artery. Superiorsagittal sinus and jugular venous pressures weremonitored in some experiments from indwellingcatheters. Both these and the arterial pressure were

mcasured using the same type of recording system asthat used for the intracranial pressure. ArterialPCO2, P02, and pH values were estimated immedi-ately before each injection of 133Xenon. End tidalCO2 was continuously monitored using an infra-redanalyser (Capnograph). Arterial packed cell volume(PCV) and haemoglobin levels were estimated atintervals throughout each experiment.

INCREASE OF INTRACRANIAL PRESSURE Intracranialpressure was raised by adding small quantities offluid to a latex balloon at approximately 30 minuteintervals, each addition of fluid being adjusted toraise the intracranial pressure by 10 to 20 mmHg.All experiments were continued until the cerebralblood flow became too low to record accurately.Two series of experiments were carried out

according to the site of the subdural balloon:

1. Infratenwtorial series (five animals) The balloonwas placed over the lateral aspect of the rightcerebellar hemisphere through a laterally placed sub-occipital burr hole.

2. Supratenitorial series (five animals) The balloonwas placed over the parietal region of the leftcerebral hemisphere via a parietal convexity burrhole.

In all experiments the cranial defects were sealedwith dental cement after balloon placement. At theend of each experiment the position of the balloonwas checked by post-mortem examination toestablish that it had not impinged directly on anymajor blood vessels or caused intracranial haemor-rhage.

RESULTS

The levels of intracranial pressure reachedbefore there was a marked reduction of cerebralblood flow differed according to the site of theballoon. In those animals with an infratentorialballoon blood flow fell at an earlier stage ofincreasing intracranial pressure (38-77 mmHg)than those with a supratentorial balloon (42-131 mmHg). In addition, the volume of fluidadded to the balloon to reach these levels ofintracranial pressure was less in the infratentorialgroup (approximately 5 ml.) than in the supra-tentorial group (14-22 ml.). Both groups ofanimals showed a marked transient bloodpressure response with each addition of fluid tothe balloon. The relation of this hypertensiveresponse to the level of intracranial pressure and

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ICP AND CBF: INFRATENTORIAL BALLOON

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CBF mi/100g/min80-

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FIG. 1. Relationship between intracranial pressure (ICP) and cerebral blood flow (CBF): Data from all fiveexperiments in each group. (a) Infratentorial balloon. (b) Supratentorial balloon.

the presence of intracranial pressure gradientshave been described in detail elsewhere (John-ston, Rowan, Harper, and Jennett, 1972b).

Control levels of cerebral blood flow, intra-cranial pressure, blood pressure, and otherparameters were similar in the two groups. Therelationship between the observed changes incerebral blood flow and intracranial pressure,cerebral perfusion pressure and cerebrovascularresistance, together with observations on auto-regulatory function will be considered separatelyfor the two groups of animals.

CBF/CPP RELATIONSHIP IN RAISED ICP INFRATENTORIAL BALLOON )

INFRATENTORIAL BALLOON Intracranial pressureand cerebral blood flow No clear relationshipbetween intracranial pressure and cerebral bloodflow emerged in this group of animals. Thevariability of the overall relationship betweenthese two parameters is exemplified in Fig. la,which plots cerebral blood flow (133Xenonclearance) against intracranial pressure for allcerebral blood flow measurements in this group.It can be seen that both high and low cerebralblood flow values occurred, in different animals,at relatively low levels of intracranial pressure,

CBF/C.PP HEL ATIONSiflP IN FiAISEO) IC:P 1SUPI'RITNIORIRL BAt LCON)

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(b)FIG. 2. Relationship between cerebral perfusion pressure (CPP) and cerebral bloodflow (CBF): Data from allfive experiments in each group. (a) Infratentorial balloon. (b) Supratentorial balloon.

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TRANSIENT CHANGES IN CPP+CBF ( INFRATENTORIAL BALLOON )

100

INFLATION

FIG. 3. Corresponding changes in60- /_-60cerebral perfusion pressure (CCP) andX0 / r 60 internal carotid artery bloodflow

mmHg - / ~_ ICAF (arbitrary units) with the transient40 40 blood pressure response at time of/ balloon inflating (infratentorial

V balloon).20L 20

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(a) (b)FIG. 4. Changes in cerebrovascular resistance (CVR), with increasing intracranial pressure (ICP). (a) Infra-tentorial balloon. (b) Supratentorial balloon.

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and the level of intracranial pressure at which asignificant and sustained reduction of blood flowoccurred was also quite variable. Thus, reduc-tion of blood flow to values of less than 30 ml./100 g/min was associated with a wide range ofintracranial pressure levels from 7 to 74 mmHg.A further feature in this group was the relativelylow level of intracranial pressure at which cere-bral blood flow had fallen to negligible levels orhad ceased altogether. The actual intracranialpressure levels at which this occurred were 38, 45,47, 37, and 77 mmHg respectively in the fiveexperiments.

Cerebral peifusion pressure and cerebral bloodflow The relationship between cerebral per-fusion pressure and cerebral blood flow wasquite uniform, in contrast with that betweenintracranial pressure and cerebral blood flowdescribed above. A linear relationship was foundbetween these two variables when all cerebralblood flow values were plotted against thecorresponding cerebral perfusion pressure valuesfor the five experiments in this group (Fig. 2a).The close correlation between cerebral perfusionpressure and cerebral blood flow was particu-larly apparent during the marked transient in-creases in blood pressure which occurred witheach injection and could be associated withrelatively little change in intracranial pressure.During these changes, cerebral blood flow in-creased and the flow changes, as measured bythe common carotid artery flow probe, exactlyparalleled the changes in blood pressure andcerebral perfusion pressure (Fig. 3). The sub-stantial alterations in blood pressure, bothhypertension and hypotension, which wereprominent in this group of animals, togetherwith the close correlation between cerebralblood flow and cerebral perfusion pressure, helpto explain the considerable variability in therelationship between intracranial pressure andcerebral blood flow.

Cerebrovascular resistance Values of cerebro-vascular resistance in this group tended toremain relatively constant over an approximateintracranial pressure range of 10 to 60 mmHg.In two of the five animals there was an initialincrease in cerebrovascular resistance with thefirst increase in intracranial pressure, this being

followed by a sharp reduction in resistance to arelatively constant level during the remainingincrease in intracranial pressure. A further twoanimals showed only an initial sharp fall incerebrovascular resistance before reaching arelatively constant level, while the remaininganimal maintained a relatively constant cerebro-vascular resistance before a final fall. Thesechanges are shown in Fig. 4a. The overallpattern was, therefore, one of quite pronouncedinitial changes in cerebrovascular resistance,followed by maintenance of a relatively con-stant level as intracranial pressure was increasedthrough the range from 10 to 60 mmHg.

Autoregulation If the relationship betweencerebral perfusion pressure and cerebral bloodflow be accepted as an indication of autoregula-tory function, it would seem that autoregulationwas lost from the time of the first addition offluid to the infratentorial balloon in all fiveanimals in this group. The relationship betweencerebral perfusion pressure and cerebral bloodflow was approximately linear for each animal,as with the composite curve from all five experi-ments (Fig. 2a). Evidence for the loss of auto-regulation is also to be found in the closecorrespondence between the transient increasesin blood pressure, cerebral perfusion pressureand cerebral blood flow which occurred witheach addition of fluid to the balloon (Fig. 3).Substantial changes in supratentorial intra-cranial pressure during the blood pressureincreases in the later stages of each experimentpresumably reflect a passive increase in cerebralblood volume associated with the change incerebral perfusion pressure. Apart from the siteof the balloon, the preparation and anaestheticwere identical in the two groups of animals inthe present study and also in the previouslyreported study (Johnston et al., 1972). In theother groups autoregulation was intact, at leastuntil the later stages of cerebral compression, soit seems unlikely that loss of autoregulation canbe attributed to factors other than the site of theballoon.

Summary There was no clear relationship be-tween intracranial pressure and cerebral bloodflow with expansion of an infratentorial balloonin this group of animals; a marked reduction of

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FIG. 5. Changes in iittra-cranial pressure (ICP),blood pressure (BP), andinternial carotid artery bloodflow wit/i addition of 0 5 ml.saline to supratentorialballoon at arrow. (Carotidartery flow in arbitrary unitsapproximating toml./100 giminl.)

20

cerebral blood flow occurred over a wide range

of intracranial pressure. In contrast, cerebralperfusion pressure and cerebral blood flow were

closely related. This applied both to the tran-sient changes in blood pressure and cerebralperfusion pressure, which occurred with eachaddition of fluid to the balloon (Fig. 3), and tothe whole period of increased intracranialpressure (Fig. 2a). After quite marked initialchanges cerebrovascular resistance tended toremain relatively constant with further increaseof intracranial pressure after the initial balloonexpansion. These findings suggest that auto-regulation was lost from the time of the firstexpansion of the balloon.

SUPRATENTORIAL BALLOON Intracranial pr-essure

and cerebral blood flow A relatively uniformrelationship between intracranial pressure andcerebral blood flow was seen during expansionof the supratentorial balloon, in contrast to thefindings with the infratentorial balloon (Fig. lb).In all five animals cerebral blood flow was main-tained during the initial phase of intracranialhypertension. Beyond a certain level of intra-cranial pressure, however, cerebral blood flowbegan to fall with further increase of intracranialpressure. The range of intracranial pressure atwhich a greater than 10% reduction of cerebralblood flow from the mean control levels hadoccurred was, however, wide (41-131 mmHg).The range was much narrower (41-61 mmHg),

if the one animal which showed exceptionalpreservation of cerebral blood flow to a highlevel of intracranial pressure is excluded. Thissingle exception nevertheless illustrates the con-

siderable variation which can occur, even in thisgroup. The levels of intracranial pressure atwhich cerebral blood flow had fallen to negligiblelevels, or had ceased altogether, were higher thanthose seen in the infratentorial group; 55, 131,75, 79, and 32 mmHg respectively in the fiveexperiments. The last value of 32 mmHg occurredin an animal in which the mean arterial pressuredropped sharply to around 40 mmHg at thetime of the major reduction in cerebral bloodflow.

Cerebral perfusion pressure and cerebral bloodflow The relationship between cerebral per-

fusion pressure and cerebral blood flow was alsorelatively uniform in this group, the flows never

falling more than 10% below control levels over

a cerebral perfusion pressure range of 32 to108 mmHg (Fig. 2b). The levels of cerebralperfusion pressure at which cerebral blood flowfell below 30 ml./l00 g/minute were 32, 36, 45,54, and 64 mmHg in each of the five experi-ments. In addition, during the transient changesin cerebral perfusion pressure caused by thetransient hypertensive episodes at the time ofeach balloon inflation, cerebral blood flow (asmeasured by the common carotid flow probe)remained constant in most instances-apart

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CBF ml/1Og/min

INFRATENTORIALBALLOON

60 40 20

SUPRATENTORIALBALLOON

0 100 80 60 40 20 0

CPP mmHg

FIG. 6. Comparison ofmean cerebral bloodflow (CBF) values for 20 mmHg ranges of cerebral pressure(CPP) with infratentorial balloon (left) and supratentorial balloon (right).

from a 30 second fall before autoregulationbecame effective (Fig. 5). During the later periodof each experiment, when cerebral blood flowhad started to fall significantly, transient bloodpressure and cerebral perfusion pressure changeswere, however, reflected in correspondingchanges in cerebral blood flow.

Cerebrovascular resistance Changes in cerebro-vascular resistance in this group of animals werealso in contrast to those seen in the previousgroup (Fig. 4b). Cerebrovascular resistancetended to fall progressively as intracranialpressure increased through an approximaterange from 10-60 mmHg. This fall was associatedwith a relatively constant level of cerebral bloodflow. Beyond this range of intracranial pressurein three animals cerebrovascular resistanceremained constant or rose slightly while in theremaining two animals cerebrovascular resist-ance continued to fall. The overall pattern inthis group was, therefore, one of a progressivefall in cerebrovascular resistance with increasingintracranial pressure, with the resultant preserva-tion of a relatively constant level of cerebralblood flow.

Autoregulation With expansion of a supra-tentorial balloon autoregulation remained effec-tive as intracranial pressure was increased up toa level of approximately 60 mmHg (Fig. lb).This corresponded to a range of cerebral per-fusion pressure of approximately 40-100 mmHg(Fig. 2b). Effective autoregulation was seenduring the marked transient changes in intra-cranial pressure and blood pressure whichoccurred at the time of each balloon inflation(Fig. 5). As the cerebral perfusion pressure fellbelow 40 mmHg autoregulation appeared to belost and cerebral blood flow then became linearlydependent on cerebral perfusion pressure. Thisloss of autoregulation did not occur as a suddentransition but seemed to take place progressivelyover a relatively narrow range of decreasingcerebral perfusion pressure, around the levelsindicated above.

Summary A relatively uniform relationshipbetween cerebral blood flow and intracranialpressure was seen with expansion of a supra-tentorial balloon, blood flow being maintainedaround control levels over a range of intra-cranial pressure up to approximately 60 mmHg.

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Similarly cerebral blood flow remained quiteconstant over a wide range of cerebral perfusionpressure down to approximately 40 mmHg(Fig. 6). During this phase of intracranial hyper-tension transient changes in blood pressure andcerebral perfusion pressure which occurred witheach addition of fluid to the balloon wereassociated with only very transient changes incerebral blood flow (Fig. 5). The maintenance ofa constant level of cerebral blood flow as intra-cranial pressure was increased was associatedwith a progressive fall in cerebrovascular resist-ance. These findings suggest that autoregulationremained effective within the ranges of intra-cranial pressure and cerebral perfusion pressureindicated. Beyond these levels autoregulationwas progressively lost and blood flow becamedirectly dependent on cerebral perfusion pres-sure.

DISCUSSION

The present results, together with those of theprevious study (Johnston et al., 1972) show thatchanges in cerebral blood flow which occur withraised intracranial pressure depend on the wayin which intracranial pressure is increased. Withinfusion of fluid into the subarachnoid spacethree phases were seen. Up to intracranialpressure levels of approximately 50 mmHg,cerebral blood flow remained constant. At intra-cranial pressure levels between 50 and 85 mmHg,a period of hyperaemia occurred with consider-able increase in cerebral blood flow. With furtherincrease of intracranial pressure a progressivefall in cerebral blood flow took place and flowappeared to be directly dependent on cerebralperfusion pressure. In the present study, withexpansion of an infratentorial subdural balloon,cerebral blood flow bore no clear relationship tointracranial pressure. Both high and low cerebralblood flow values were recorded through a widerange of intracranial pressure. Cerebral bloodflow in animals with an infratentorial balloondid, however, correlate closely with cerebralperfusion pressure throughout, the relationshipbetween these two parameters being almostlinear. Raising intracranial pressure by expan-sion of a supratentorial subdural balloon pro-duced a third type of response: cerebral bloodflow being maintained at a relatively constantlevel through a wide range of both intracranial

pressure (0-60 mmHg) and cerebral perfusionpressure (100-40 mmHg). Beyond these levelsblood flow became progressively more directlydependent on cerebral perfusion pressure. Thediffering relationships between cerebral bloodflow and cerebral perfusion pressure with thetwo balloon sites are contrasted in Fig. 6. Theseobservations, using different methods of raisingintracranial pressure under the same basicexperimental conditions and over the sameperiods of time, help to explain the variabilitywhich is such a feature of previous experimentaland clinical studies of the inter-relationshipbetween intracranial pressure and cerebral bloodflow (Kety et al., 1948; Greenfield and Tindall,1965; Huber, Meyer, Handa, and Ishikawa,1965; Langfitt et al., 1965; Zwetnow, 1970;Lowell and Bloor, 1971).

It seems, therefore, that the mechanismswhich control cerebral blood flow behavedifferently according to the cause of the increasein intracranial pressure. The two major factorscontrolling cerebral blood flow are the cerebralperfusion pressure, defined as the differencebetween the mean systemic arterial pressure andthe mean intracranial pressure (Zwetnow, 1968)and the cerebrovascular resistance, defined asthe ratio of cerebral perfusion pressure tocerebral blood flow. Both factors may beinfluenced by a wide variety of further factors.Quite apart from this the definitions themselvesdepend on certain assumptions, some of whichmay be open to question. It is probable that it isin the differing effects which different methods ofraising intracranial pressure have on these fac-tors that the explanation of the variability inprevious observations is to be found.The level of cerebral perfusion pressure at a

particular level of intracranial pressure dependson the level of systemic arterial pressure. Thetime course and magnitude of the responsediffered according to the method used to in-crease intracranial pressure so that at a givenlevel of intracranial pressure cerebral perfusionpressure differed in each type of intracranialhypertension. Further, the definition of cerebralperfusion pressure depends on two assumptions;firstly, that the mean arterial pressure representsthe effective cerebral arterial inflow pressure, and,secondly, that intracranial pressure representsthe effective venous outflow pressure. It is

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probable that neither of these assumptions iscompletely justified. The magnitude of thearterial pressure drop between extra- and intra-cranial vessels may vary, in states of raisedintracranial pressure, both with changes inarterial pressure and with changes in intra-cranial pressure (Kanzow and Dieckhoff, 1969).The approximation of the intracranial pressureto the effective venous outflow pressure may alsodiffer according to the level of intracranialpressure. A close correlation is known to existbetween intracranial pressure and cortical sub-arachnoid vein pressure over the lower ranges ofintracranial pressure (Shulman, 1965; Shulmanand Verdier, 1967). This relationship has not yetbeen explored, however, for the higher ranges ofintracranial pressure, although such an investiga-tion is being carried out in this laboratory. Inaddition, marked morphological changes havebeen observed in the major dural venous sinusesin extreme intracranial hypertension (Wright,1938; Kinal, 1964; Shapiro, Langfitt, andWeinstein, 1966; Osterholm, 1970). Such changesmay have an important bearing on venous out-flow pressure. Finally, doubt has been raised asto whether intracranial pressure itself remainsuniform, even within the same intracranialcompartment, in states of raised intracranialpressure (Weinstein, Langfitt, Bruno, Zaren, andJackson, 1968; Brock, Beck, Markakis, andDietz, 1972).

Calculated values for cerebrovascular resist-ance have also shown a different pattern ofchange according to the method used to in-crease intracranial pressure. Expansion of aninfratentorial subdural balloon led to a sharpinitial change followed by a relatively constantlevel of cerebrovascular resistance, whereas asupratentorial subdural balloon gave rise to aprogressive fall in cerebrovascular resistance(Figs 4a and b). In the previous study, usinginfusion of fluid into the cisterna magna, cerebro-vascular resistance fell during the initial increaseof intracranial pressure, than remained constantduring the hyperaemic phase.The patterns of change in vascular resistance

reflect the relative influence of the factors whichcontrol resistance and capacitance in the cerebralvessels in different forms of intracranial hyper-tension. A localized supratentorial mass may, bycausing brain shift, lead to distortion and

mechanical obstruction of the superficial corticalveins. An infratentorial mass may, by localstimulation of the brain-stem, have markedinfluence on sympathetic activity and thereforeinfluence cerebral blood flow by altering thediameter of both the extraparenchymal intra-cranial vessels and the large vessels in the neck(Harper, Deshmukh, Rowan, and Jennett, 1972).Raised intracranial pressure due to infusion offluid into the subarachnoid space may beassociated with changes in the local vesselenvironment, thus altering the response of thesevessels to local metabolic stimuli.The changes in vascular resistance which have

been considered above and which act to pre-serve blood flow in the face of a changing cerebralperfusion pressure are subsumed under the termautoregulation. In a previous study it was shownthat autoregulation was effective in maintaininga relatively constant blood flow over an intra-cranial pressure range of approximately 0-50mmHg (Johnston et al., 1972). At higher levelsof intracranial pressure, autoregulation stillseemed to be effective, during the period ofhyperaemia, although the blood flow appearedto be reset at a higher level for a given value ofcerebral perfusion pressure. After the period ofhyperaemia autoregulation was lost and bloodflow became directly dependent on cerebral per-fusion pressure. In the present study, with thesupratentorial balloon, autoregulation remainedintact down to cerebral perfusion pressurevalues around 40 mmHg before being lost. Withthe infratentorial balloon, however, auto-regulation appeared to be lost from the time ofthe first balloon expansion.

Three distinct patterns of response weretherefore seen but, while these patterns wereconsistent within each group, there is, as yet, noclear evidence as to the cause of these differencesof autoregulatory function. The findings, may,however, be of some value in elucidating thenature of autoregulation in the cerebral circula-tion. Previously, attempts have been made todiscover a single central mechanism which isresponsible for autoregulation. While this maybe possible if the term is used in the narrow sense,referring to the mechanism by which the diameterof the cerebral resistance vessels (arterioles) iscontrolled (Green, Rapela, and Conrad, 1964), itseems much less possible if autoregulation is con-

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sidered in the wider sense as the overall preserva-

tion of blood flow in the face of possible com-

promising factors. The present results are, infact, in harmony with the view that a number ofcomplex inter-related compensatory mechanismsexist to preserve blood flow in situations inwhich the blood supply to the brain may bejeopardized by increased intracranial pressure.It seems likely that the form which the overallcompensatory response takes will depend,among other factors, on the cause and timecourse of the increase in intracranial pressure.

It is apparent from these considerations thatattempts to define a comprehensive quantitativerelationship between either intracranial pressure

or cerebral perfusion pressure and cerebralblood flow will be unsuccessful. Further, whilethe different methods used to increase intra-cranial pressure in these studies may be said tostimulate different clinically occurring lesions,there is no certainty that the patterns of responsedescribed are directly applicable to the clinicalsituation. The clinician remains on very un-

certain ground when trying to gauge cerebralblood flow from measurements of intracranialpressure. In conclusion it should be emphasized,therefore, that, while raised intracranial pressuremay lead to a reduction in cerebral blood flow,there is no justification at present for attemptingto draw quantitative conclusions about cerebralblood flow from clinical measurements of eitherintracranial pressure or cerebral perfusionpressure. Before this is possible, much more re-

mains to be learned about the mechanism ofautoregulation, the factors which may affectautoregulation, and the assumptions underlyingthe concepts of cerebral perfusion pressure andcerebrovascular resistance.

The authors' thanks are due to Miss I. Sanholm,Mr. G. Littlejohn, and the other members of thetechnical staff of the Wellcome Institute.

REFERENCES

Brock, M., Beck, J., Markakis, E., and Dietz, H. (1971). Theimportance of intracranial pressure (ICP) gradients forregional cerebral blood flow (rCBF). Panminerva Medica,13, 194-195.

Green, H. D., Rapela, C. E., and Conrad, M. C. (1963).Resistance (conductance) and capacitance phenomena interminal vascular beds. In Handbook of Physiology.Vol. 2, Sect. 2. Edited by W. F. Hamilton and P. Dow.Williams and Wilkins: Baltimore.

Greenfield, J. C., Jr., and Tindall, G. T. (1965). Effect ofacute increase in intracranial pressure on blood flow in theinternal carotid artery of man. Journal of Clinical Investiga-tion, 44, 1343-1351.

Harper, A. M., Deshmukh, V. D., Rowan, J. O., andJennett, W. B. (1972). Experimental studies on the influenceof the sympathetic on cerebral blood flow. Archives ofNeurology, 27, 1-6.

Huber, P., Meyer, J. S., Handa, J., and Ishikawa, S. (1965).Electromagnetic flowmeter study of carotid and vertebralblood flow during intracranial hypertension. Acta Neuro-chirurgica, 13, 38-63.

Johnston, I. H., Rowan, J. O., Harper, A. M., and Jennett,W. B. (1972a). Raised intracranial pressure and cerebralblood flow. I. Cisterna magna infusion in primates.Journal of Neurology, Neurosurgery, and Psychiatry, 35,285-296.

Johnston, I. H., Rowan, J. O., Harper, A. M., and Jennett,W. B. (1972b). The blood pressure response to raisedintracranial pressure. Clinical and experimental observa-tions. (In preparation.)

Kanzow, E., and Dieckhoff, D. (1969). On the location ofvascular resistance in the cerebral circulation. In CerebralBlood Flow, pp. 96-97. Edited by M. Brock, C. Fieschi,D. H. Ingvar, N. A. Lassen, and K. Schurmann. Springer:Berlin.

Kety, S. S., Shenkin, H. A., and Schmidt, C. F. (1948). Theeffects of increased intracranial pressure on cerebralcirculatory functions in man. Journal of Clinical Investiga-tion, 27, 493-499.

Kinal, M. E. (1966). Infratentorial tumors and the duralvenous sinuses. Journal of Neurosurgery, 25, 395-401.

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