relationships between cerebral perfusion...

Relationships Between CerebralPerfusion Pressure and RegionalCerebral Blood Flow in Patients WithSevere Neurological DisordersBY M. PETER HEILBRUN, M.D.,* PAUL BALSLEV JORGENSEN, M.D.,AND GUDRUN BOYSEN, M.D.

Abstract:RelationshipsBetweenCerebralPerfusionPressureand RegionalCerebralBlood Flowin PatientsWith SevereNeurologicalDisorders

• Three patients, one with a recurrent brain tumor, one with a severe braincontusion, and one with a brain abscess, are described who had continuousmonitoring of the intracranial pressure with epidural and/or ventricularpressure transducers, continuous monitoring of the blood pressure, and periodicregional cerebral blood flow (rCBF) studies by the intra-arterial 133Xenonmethod. A fourth patient with a severe brain contusion is described who hadonly blood pressure monitoring and rCBF studies. By measuring the regionalcerebral blood flow and by testing autoregulation through changes in cerebralperfusion pressure and arterial Pco.>> it ' s possible to reveal critical levels ofcerebral perfusion pressure in the supratentorial compartment. Such measure-ments allow more rational evaluation of methods for control of increasedintracranial pressure. The data point out that monitoring of systemiccardiorespiratory parameters for signs of cerebral compression is generallyinadequate. The fact that pressure gradients may exist within the craniospinalenclosure is discussed. For this reason, before valid conclusions can be maderegarding brain stem circulatory impairment at the tentorium and in theposterior fossa, the present regional techniques must be applied to thesecompartments also.

ADDITIONAL KEY WORDS3:t3Xenon intra-arterial method

autoregulation intracranial pressure

Introduction• Cerebral dysfunction associated with in-creased intracranial pressure has been relatedto ischemic hypoxia. This explanation wasimplied by Leyden in 1866 in his first studiesof the effects of cerebral compression and hasbeen demonstrated experimentally in manystudies since then.1 Kocher and Cushing werethe first to stress that the focal brain stem

From the Department of Neurosurgery, SurgicalDepartment D, Rigshospitalet, Department of Neuro-surgery and Department of Clinical Physiology,Bispebjerg Hospital, Copenhagen, Denmark.

Supported by the Van Wagenen Fellowship.'Present address: Division of Neurological Sur-

gery, University of Utah Medical Center, Salt LakeCity, Utah, 84112.

Stroke, Vol. 3, March-April 1972

ischemia which occurs in these conditionsinvokes systemic circulatory responses in anattempt to compensate for the hypoxia.2-3

However, Browder and Meyers4 showed manyyears ago that these systemic circulatorychanges occur only at late stages of severebrain compression. More recent studies byJohnston et al.,B with continuous monitoring ofthe intracranial pressure and the systemicarterial pressure, have stressed the inconstantrelationship between these two pressures andthe inadequacy of the "Cushing" response. Forthese reasons monitoring the parameters ofblood pressure, pulse and respiration is notsufficient to estimate the degree of circulatoryimpairment.

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HEILBRUN, JORGENSEN, BOYSEN

Since it is now possible to measureroutinely the intracranial pressure,0-7 theclinician can have a continuous measurementof the cerebral perfusion pressure as it can beeasily calculated as the difference between themean intracranial pressure and the meanarterial blood pressure. If the relationships ofthese pressures are then correlated withcerebral blood flow studies, one can betterjudge the degree of circulatory impairment ofbrain tissue.

Cerebral Blood Flowand Cerebral Perfusion PressurePast studies relating cerebral blood flow tointracranial pressure must be considered inade-quate because the cerebral perfusion pressurewas estimated by the systemic arterial pressurealone, or the lumbar cerebrospinal fluidpressure alone. The value of these studies,however, lies in the findings that the blood flowto the brain stayed relatively constant untilhigh levels of intracranial pressure or lowlevels of arterial pressure were reached, aphenomenon commonly termed autoregula-tion.8' 8 Noell and Schneider10 demon-strated in animals that cerebral blood flowdecreased after the mean arterial pressuredecreased to 60 to 70 mm Hg. Ryder et al.11

demonstrated that in some patients the lumbarspinal fluid pressure could be increased to 70mm Hg without clinical symptoms occurringand without an effect on cerebral blood flow.

Zwetnow12 was the most recent worker torelate cerebral blood flow to quantitativemeasurements of the cerebral perfusion pres-sure which he calculated from simultaneousarterial and intracranial pressure recordings.He showed that when the intracranial pressurewas raised uniformly by increasing the cerebro-spinal fluid pressure, no decrease in flowoccurred until the intracranial pressure reached100 mm Hg and the cerebral perfusionpressure was narrowed to 30 to 50 mm Hg. Hisstudies demonstrate very clearly that thenormal brain does not lose its capacity forautoregulation until the perfusion pressure isnarrowed markedly. Zwetnow also pointed outanother very important factor about autoregu-lation. He demonstrated that the arterial PCOo

is a most critical factor in regulation ofarteriolar tone and must also be considered inany definition of autoregulation abnormalities.

182

For example, at hypercapnia the arterioles willbe dilated and will not be able to autoregulateflow even when the perfusion pressure is in anormal range.13 This phenomenon is clearlyillustrated in figure 1 showing that at high PCOn

flow passively follows the perfusion pres-sure.

In pathologic states, particularly acutebrain injuries, autoregulation is also im-paired.14"17 The mechanism for this type ofimpaired autoregulation may be similar to themechanisms in the hypercapnic state. Thefindings of an autoregulatory plateau have not

rCBF ml/100g/min

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FIGURE 1

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The rCBF is related to perfusion pressure at variousranges of arterial Pco . The upper solid symbols and

lines are from Zwetnow1' and are the rCBF valuesin the dog cortex. The lower open symbols and dashedlines are the rCBF' 10 values for the four patientsdescribed in this study.



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PERFUSION PRESSURE AND rCBF

been uniform in the literature. The experimen-tal studies of Langfitt et al.38 and Baldy-Moulinier et al.in showed that the blood flowdecreased concomitantly with intracranialpressure increases. These findings are bestexplained by loss of autoregulation associatedwith brain lactoacidosis. Combinations ofperfusion pressure, COj reactivity abnormali-ties, and focal changes in autoregulationexplain the paradoxical flow changes aroundfocal lesions. Brock20 and Reulen21 havedemonstrated areas of both decreased andincreased flow around focal cold or pressurelesions which cause combinations of tissuehypoxia with subsequent lactoacidosis, edemaand impaired autoregulation. These studiesalso point out that the state of autoregulatoryprocesses can be different in various areas ofthe brain. Moreover, the persistence of im-paired autoregulation after an acute braininjury can vary.0'22' 'a

It must also be pointed out that in manyconditions low cerebral blood flow is foundwhich is not associated with impaired autoregu-lation or CO^ reactivity. In conditions in whichcerebral function is depressed, such as drugeffects or states in which the brain hassustained past damage with loss of neuronaltissue, the metabolic rate of the brain will below and the cerebral blood flow concomitantlydepressed.24' 2r>

The context of the prior studies suggeststhat perfusion pressure affects cerebral bloodflow when either the perfusion pressure is lowor COo reactivity is absent. When autoregula-tion is impaired, control of the perfusionpressure is necessary to prevent decreases ofthe blood flow to levels which cause tissuehypoxia.10 This is particularly important inacute brain injuries in which it cannot beassumed that the cerebral blood flow isdecreased due to a low metabolic demand.

The purpose of this report is to emphasizethe necessity of monitoring the cerebralperfusion pressure and defining regional cere-bral blood flow characteristics in neurosurgicalpatients. This is of increasing importance withthe more prevalent use of controlled respira-tion in the treatment of central nervous systemlesions.20

MethodsThe findings presented in this paper are selectedfrom four of a series of 13 patients, all with severe


brain disorders, 12 of whom were having theintracranial pressure monitored. The etiology ofthe central nervous system lesion was trauma,recurrent tumor, and brain abscess. Each of thepatients had mechanically assisted respirationduring part or all of the time he was studied. Twoof the described patients died and two survived.The remaining nine patients are not described asthe intracranial pressure was so high that thecerebral blood flow was unmeasurable. Theintracranial pressure was monitored with aminiature pressure transducer which was intro-duced between the bone and the dura through acoronal perforator opening.27 The transducer wascalibrated prior to insertion and recalibrated afterremoval. The time of recording varied fromseveral hours to more than ten days. Themaximum zero drift of the transducer was 5 mmHg per 24 hours of recording. However, the zerodrift over the longest recording time of ten dayswas only 15 mm Hg. Two of the four patients hadthe epidural pressure and ventricular pressuremonitored simultaneously. Generally the epiduralpressure was 5 to 15 mm Hg higher than theventricular pressure. This has also been theexperience in a large series of comparisons exceptin a few cases where the two pressures are equal.The characteristics of the epidural or brainsurface pressure have recently been discussed bySchettini et al.28 Other comparisons of ventricularpressure and epidural pressures have reportedsimilar differences.2I>

The normal intracranial pressure was estab-lished as 1 to 10 mm Hg in accordance with thelarge series of Lundberg.0 In patients withelevated intracranial pressure, the pressure record-ing showed an increase in the amplitude of theperiodic changes which normally correspond to anintegration of the arterial, venous and respiratorypulsations. When the intracranial pressure becamemarkedly elevated, it directly followed changes inthe arterial pressures. In this situation the braintissue appears to act as a passive transmitter of thearterial pressure. This condition was defined asloss of regulation of intracranial pressure.

The mean intracranial pressure was deter-mined by intermittent mechanical damping of theintracranial pulsations or calculated as one-half ofthe difference between the high and low peaksadded to the height of the low peak. The arterialpressure was monitored by either the standard cufftechnique or by an intra-arterial catheter in theradial or the internal carotid artery in patientswho had reached a terminal state. The cerebralperfusion pressure (PP) was calculated as thedifference between the mean intracranial pressure(ICP) and the mean arterial blood pressure(MABP).

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The regional cerebral blood flow (rCBF), asmeasured by the 188Xenon method, has beendescribed extensively in previous publica-tions.115' 3°-32 In the patients who were notin terminal condition, the CBF study wasperformed in conjunction with cerebral angiogra-phy. A Teflon catheter, through which 2 to 3mCi of 133Xenon dissolved in saline was injected,was placed percutaneously in the internal carotidartery by the Seldinger technique. The clearancewas recorded with 14 Nal (TI) scintillationdetectors placed over the cranial vault. In patientsconsidered to be in a terminal state, the internalcarotid catheter was left in place for up to 11hours for continuous monitoring of the intra-arterial pressure and for multiple rCBF studiesdepending on changes in both the patient'scondition and the perfusion pressure. The rCBF10was calculated by the height over the area methodusing the ten-minute clearance curve.30 The rCBFinitial was calculated from the initial part of theclearance curve as described by Olesen et al.,32

who have demonstrated the close correlationbetween the flow values calculated by ten-minuteand initial slope methods. With each rCBFdetermination arterial blood was taken fordetermination of the Poo,, and O2 content. Inseveral cases, jugular puncture was performed andjugular venous blood removed for determinationof the O-, content and calculation of the arterial-venous Oo difference. When this determinationwas made, the oxygen utilization (CMRO2) wascalculated as the multiple of the mean rCBF andthe ipsilateral A-V O2 difference.

Generally each series of rCBF studies wasfollowed or preceded by a cerebral angiogram.

Case ReportsCASE 1

This 52-year-old woman had a right frontaloligodendroglioma removed nine years prior toadmission. She did well until one year beforeadmission when she gradually developed markedmental changes. She was admitted in a state ofstupor. Angiography and air encephalographyshowed evidence of a recurrent right frontaltumor. It was elected not to reoperate. The patientgradually deteriorated over 24 hours. The epiduralpressure transducer was placed over the righthemisphere and a closed left ventricular puncturewas performed, without removal of fluid, with acatheter attached to another pressure transducer.The left internal carotid artery was cannulated.Clinical examination at that time showed anunconscious patient who reacted to noxiousstimuli with purposeful movements of all extremi-ties. Cranial nerve examination showed the pupilsfixed and dilated with absent eye movements.

Corneal and cough reflexes were present. Sponta-neous respiration was present but was assistedwith a volume respirator. The first flow study overthe hemisphere opposite the tumor was performedtwo hours after pressure recording was started. Atthat time no cranial nerve reflexes could anylonger be elicited although some spinal reflexespersisted. The EEG showed slow cortical activity.The PP was 70 mm Hg with the ICP elevated to40 mm Hg and the MABP to 110 mm Hg. TherCBF10 was in average 21 ml/100 gm/min withno regional differences. The arterial PCOo wasreduced to 22 mm Hg and the A-V O2 differencewas 11.4 vol%, showing a normal vasoconstrictorresponse to hypocapnia. In spite of this appear-ance of normal vessel CO2 reactivity there wasloss of regulation of ICP at this stage in that theintracranial pressure followed both the rapid andslow changes in arterial pressure. This findingsuggested a pressure passive vascular bed. Over aperiod of two and one-half hours the ICPgradually increased to 80 mm Hg while theMABP showed a Cushing response and alsoincreased, maintaining the PP at 50 to 60 mm Hg.This rise was followed by an abrupt fall of theMABP to 80 mm Hg. The ICP fell also but to alesser degree so that the PP narrowed to 15 mmHg. 1S3Xenon was injected and the flow(rCBFlnlt|nl value) was 6 ml/100 gm/min. Aplasma expander was administered intravenously.However, the MABP and the ICP continued tofall, narrowing the PP further. The MABP wasthen raised with metaraminol bitartrate. Tenminutes following the ]33Xenon injection the PPwas 22 mm Hg and lsflXenon clearance started toincrease. Removal of ventricular fluid furtherincreased the PP to 80 mm Hg resulting in afurther increase in flow as determined byincreased 183Xenon clearance.

The MABP remained high but the ICPgradually increased over a period of two hoursfollowing which the MABP fell. It was againelevated with vasopressor agents but the PPremained narrowed at 15 mm Hg. At this stage133Xenon was injected. The flow (rCBF|nltlnl)averaged 9 ml/100 gm/min. Withdrawal ofventricular fluid twice, at three-minute intervals,resulted in increases of the PP to 25 mm Hg and50 mm Hg followed by increases of 1S3Xenonclearance rate. The ICP continued to climb backup. When the PP reached zero, 188Xenon wasinjected again. The appearance of the clearancecurve suggested that the l:t3Xenon did not enterthe cranial vault, but refluxed into the externalcarotid system. Aortocervical angiography showedno entrance of contrast material into the cranialvault.

184 Stroke, Vol. 3, March-April 7972


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CommentThis case illustrates the effect of perfusionpressure variations on blood flow in brain tissuesubjected to increased ICP. The PP studied rangedfrom normal values to zero with most values inthe interval where abolished autoregulation isexpected from animal studies. As shown in figure2, the changes in perfusion pressure were dueboth to fall in blood pressure and to increasingintracranial pressure. The absence of regional flowdifferences is probably explained by the fact thatthe tumor was located in the opposite hemisphere.However, global depression of flow was present ata time when the perfusion pressure was 70 mmHg, i.e., a value which would allow a normal flowin healthy brain tissue. However, a significantfactor in decreasing the flow to 21 ml/100gm/min at this stage may have been thehyperventilation which lowered the arterial Pco.,to 22 mm Hg. The high A-V O2 difference of11.4% resulting in oxygen utilization of 2.4ml/100 gm/min, 73% of normal, tends to

confirm the conclusion that the cerebral vessels atthis point displayed a normal reactivity tohypocapnia. At two and one-half hours, theperfusion pressure was the dominant factorreducing flow. This is shown in figure 3. Thesystemic pressure fell precipitously, narrowing theperfusion pressure to 15 mm Hg. The initialclearance of ls3Xenon was slow with a calculatedrCBF initial of 6 ml/100 gm/min. The perfusionpressure was then increased first by raising thearterial pressure with a vasopressor, and second,by ventricular drainage. With both maneuvers, anincrease in 133Xenon clearance occurred (evidenceof an increase in flow).

CASE 2

This 26-year-old woman was admitted in comafollowing a suicide attempt in which she jumpedfrom the third floor. Initial examination showed acomatose woman with marked nasopharyngealbleeding. The blood pressure was 60/40, the pulserate 130/min, and the respirations rapid. The ICPwas not measured. Both pupils were dilated and

MW 1 71 CEREBRAL BLOOD FLOW and PERFUSION PRESSURE

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186

FIGURE 2

Case 1, illustrating the time course of cerebral perfusion pressure cluviges, CBF studies andaortocervical arteriography. The upper two solid lines illustrate the duration of cephalicand spinal reflexes. The third solid line illustrates the time of EEG recording and tlieinterpretation.



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• w 171 C I F .nd PERFUSION PRESSURE

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Case 1, illustrating the logarithmic display of the ""Xenon clearance curves, from which therCBFinWal is calculated, related to the cerebral perfusion pressure. CBF 1 shows the normalclearance curve with a stable perfusion pressure, while CBF 2 and CBF 3 show the increasesin clearance which occur when the perfusion pressure is increased by ventricular drainage.

fixed and there were absent eye movements.Cough reflex was present. She repelled noxiousstimuli with appropriate movements of all extrem-ities and had normal tendon reflexes. Anendotracheal tube was placed and multiple bloodtransfusions were administered. Skull filmsshowed frontal comminuted fractures through thesinuses and orbital roofs. A chest film showed afractured sternum and extremity films showedfractures of the left femur and the left radius. Aright carotid arteriogram showed a small vertexepidural hematoma. Following angiography theCBF was measured. The MABP at the first CBFstudy was 40 mm Hg and the rCBF10 was 37.5ml/100 gm/min. With rapid intravenous infusionof whole blood and balanced lactate solution over30 minutes, the MABP raised to only 50 mm Hg.Nevertheless, the rCBF]ft was increased to 49.7ml/100 gm/min. Both studies showed focal areasof decreased flow frontally. The arterial PCOo was42.5 mm Hg and 40.4 mm Hg at the first andsecond study, respectively. The A-V O2 differencemeasured simultaneously with the second studywas 4.2 vol %, yielding a CMROo of 2.07 ml/100gm/min. Following the CBF measurements arepeat chest film showed a left pneumothorax anda chest tube was placed. Her respirationsimproved slightly and the blood pressure rose tonormal levels. The following day the pupils were


small and reactive and dysconjugate eye move-ments were present. The patient could followsimple commands but was stuporous. She contin-ued to have respiratory insufficiency and followinga tracheotomy was treated with assisted ventila-tion for four days during which the arterial P0 0 oaveraged 32 mm Hg. She gradually improved, andsix weeks following the injury, she was alert withnormal speech and good mentation. Bilateraldysconjugate gaze was still present. Her fractureswere healing well. She was eventually dischargedfor rehabilitation.

CommentThis case illustrates most dramatically the criticalrange of perfusion pressure superimposed on anacutely damaged brain which has autoregulationabolished clearly on the basis of a low perfusionpressure but also possibly on the basis of tissueacidosis associated with trauma. With an MABPof 40 mm Hg the rCBF10 was 37.5 ml/100gm/min. A minimal increase of the bloodpressure to 50 mm Hg resulted in a flow increaseto 49.7 ml/100 gm/min. If one considers that atthis stage the ICP at the lowest would have been10 mm Hg, one could assume that the PP was notmore than 40 mm Hg. Although the flow wasnormal at this stage the A-V O2 was decreased to4.2 vol % with a CMRO2"of 2.07 ml/100

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gm/mni, 63% of normal. With this evidence ofsubnormal oxygen extraction in the presence ofnormal flow, one can conclude that a "luxuryperfusion state" existed presumably from tissueacidosis since the PC0;) was normal.33 Thequestion can be asked if this high flow could infact be deleterious, and once the blood pressurewas elevated to normal, would the brain withpresumably even higher flow be prone towardedema formation. Although the patient wasimproved on the second post-trauma day, hermost marked improvement occurred during thefour-day period of assisted ventilation. During thisstage she was rendered mildly hypocapnic.Although no flow or A-V O2 difference measure-ments were made during this treatment, one couldpresume that the relatively high flow state wascounteracted, as she progressed to completerecovery except for mild ocular palsies.

Case 3This 16-year-old boy was struck by an automobilewhile riding his bicycle. He had no severecomplaints initially, but was found unconscious inhis bed the next morning. After a right frontalepidural hematoma was removed through a burrhole at a local hospital, he was transferred to theneurosurgical service where the frontal lobe wasfurther decompressed by hematoma removalthrough a craniotomy. Following surgery heremained unconscious with decerebrate posturingand active tendon reflexes. Cranial nerve examina-tion showed the left pupil small, the right pupildilated, both nonreactive, absent eye movements,and absent vestibular response to ice water.Corneal and cough reflexes were present. Sponta-neous respirations were present but inadequate; hewas hyperventilated with a volume respiratorthrough a nasotracheal tube. Recording of theepidural and intra-arterial pressure was started 30

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FIGURE 4

Case 3, illustrating the time course of cerebral perfusion pressure narrowing, CBF studiesand aortocervical arteriography. The upper solid lines illustrate the duration of cephalic andspinal reflexes. The third solid line illustrates the time of EEG recording and the interpre-tation. It can be seen that the perfusion pressure narrows to zero and remains negative twominutes after CBF 5 is started.



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hours after the injury (fig. 4). The first CBF studywas performed one hour later, at which time thePP was 70 mm Hg. The average rCBF10 was 42ml/100 gm/min. The Ppo,, was 24 mm Hg.Marked interregional differences were present withareas of rapid and multiexponential flow in thefrontal region underlying the evacuated hemato-ma. The average rCBF,nltlal was 68 ml/100gm/min in the frontal area and 31 ml/100gm/min in the parietal area. The A-V O2difference was 3.7 vol % and the CMR02 was1.55 ml/100 gm/min. These measurements sug-gested a "luxury perfusion" syndrome. His clinicalcondition did not change. However, it wasconsidered that this respiratory activity wassufficient and the respirator assistance was stoppedsix hours later. An angiogram at that time showedabsence of a hematoma. An early vein was notedin the frontal area. The second CBF study wasperformed 11 hours after the first. At that time hisclinical condition was unchanged. The PCOo hadincreased from 24 mm Hg to 36 mm Hg. The PPhad decreased to 42 mm Hg due to a decrease inthe MABP rather than to a change in the ICPwhich remained at 40 mm Hg. The averagerCBF]() decreased minimally to 39 ml/100gm/min. The regional differences were lessmarked in this study due to an increase in therCBFlnlUn| to 44 ml/100 gm/min in theparietal region compared to a slight decrease inthe frontal region to 62 ml/100 gm/min. Thisfinding in conjunction with the first CBF studydemonstrated hyperemia with impaired CCXreactivity and loss of autoregulation in the frontalregions and better preservation of autoregulationand CO., reactivity in the parietal area. The A-VO. was 5.85 vol % with the CMRO. 2.27 ml/100gm/min. Although the patient's prognosis waspoor, it was felt that his clinical condition hadremained stable, and the intracarotid catheter wasremoved. Over the next two days the ICPremained between 20 and 40 mm Hg, with theMABP between 80 and 100 mm Hg. His clinicalstate remained unchanged. On the third day afteradmission ICP further increased and he developeddifficulty with breathing over a period of 30minutes, necessitating respiratory assistance witha volume respirator. At that time both pupils werefixed and dilated. Corneal reflexes were stillpresent along with the decerebrate posturing andupper extremity tendon reflexes. The right internalcarotid artery was recannulated. The ICP tendedto follow the rapid variations in the MABP andslower variations in respiration, demonstrating theloss of regulation of ICP which occurs atincreased ICP levels. When the PP narrowed to 40mm Hg (ICP to 80 mm Hg) the third CBF studywas performed. The mean rCBF10 was 31 ml/100gm/min with similar interregional differences


recorded (as noted in the two earlier studies). Nojugular blood was obtained for O;. analysis. Thefourth CBF study was performed 50 minuteslater, at which time the MABP had fallen to 75mm Hg narrowing the PP to 15 mm Hg. Themean rCBF10 was 20 ml/100 gm/min. Interre-gional differences were no longer seen. Theclearance curves appeared monoexponential. Thisfinding was interpreted as a preferential decreasein the fast flow compartments as comparedto slow compartments. The clinical statewas unchanged. The EEG showed slow de-pressed cortical activity. The fifth CBF studywas performed when the PP narrowed to 8 mmHg. The mean rCBFln was 4.3 ml/100 gm/min.However, two minutes after the injection of1!t;lXenon, the perfusion pressure narrowed to zeroand no further clearance of 188Xenon occurredover the next ten-hour observation period,implying that complete and permanent cessationof blood flow was recorded in this study. TheEEG performed ten minutes after the 188Xenoninjection was flat. No further corneal or coughreflexes were present and no movements wereelicited with noxious stimuli. Upper extremitytendon reflexes persisted, however.

Aortocervical angiography showed no passageof contrast material into the cranial vault. Onehour after the angiogram, with a negative PP of—10 mm Hg, no further ls:lXenon could be in-jected into the cranial vault. Cardiac action ceasedfive hours later.

CommentThis case demonstrates a wide spectrum ofabnormalities. There are regional differences inflow, autoregulation, and CO2 reactivity when theperfusion pressure is above 40 mm Hg. However,when the perfusion pressure falls below thenormal autoregulatory range, the flow in thewhole hemisphere becomes dependent on theperfusion pressure. This is shown in figures 5 and6. The first CBF study showed that in the rightcerebral hemisphere, the one most directlysubjected to compression by the epidural hema-toma, the frontal and parietal areas had signifi-cantly different flow patterns. As the arterial Pc0.,was 24 mm Hg, one could conclude that in thefrontal area loss of autoregulation and COoreactivity was present, while in the parietal areathe vessels were able to constrict to thehypocapnic stimulus. This conclusion was con-firmed by the second study, at which time thePQO., was elevated to 36 mm Hg and the PPnarrowed to 42 mm Hg and flow increased in theparietal area but decreased in the frontal area. Atthis PP and PCOo level the luxury perfusioncondition was relatively improved with an in-crease of CMRO2 to 2.27 ml/100 gm/min. In

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ksfRELATKJUSHIPS/POfUSIW PRESSURE

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FIGURE 5

Case 3, illustrating the logarithmic display of the first two minutes of the regional 13SXenonclearance curves from which the rCBFil>itial is calculated. In CBF 1 to CBF 3 the markeddifferences in the slope of the curves between the frontal and parietal areas are obvious. InCBF 4 the rate of clearance is decreased (lower flow) and no further differences are noted.The average rCBF10 of all channels, the average rCBFinitlal in the frontal and parietalregions, and the MABP, ICP, PP, and Pco are noted for each study.

spite of the apparently adequate oxygenation, atthree days the clinical parameters suggested thatthe brain stem dysfunction had seriouslyworsened. Following a period of erratic breathingspontaneous respirations had ceased and thepupils were dilated and nonreactive. Whathappened in the right cerebral hemisphere duringthe two days between the second and third flowstudies? Both the PP and the PCOo had remainedrelatively constant. However, the constant PP wasdue to the increase in MABP as a response to theICP which had doubled to 80 mm Hg. This pointsout the importance of watching the ICP andMABP as well as the PP. It seems obvious thatbrain swelling and further brain stem compressionhad developed. The third CBF study confirmedthis, in that with essentially no change inperfusion pressure and only a slight elevation inPCo2, the rCBFlnltlaI had markedly decreasedin both the frontal and parietal areas. The flowstudies demonstrated that at this stage the PP was

190

the dominant factor controlling the flow. With anincrease in Pco.,. the ICP rose further narrowingthe PP. Metabolic factors such as POo., andacidosis no longer predominated. A pressurepassive system was present in which the flowdepended solely upon the PP with decreases,rather than increases, in flow in response toelevation of PCOo. As the PP approached zero,decreasing hemisphere flow to the range of zerowas recorded.

Case 4This 52-year-old man was admitted for evaluationof seizures. He showed the effects of chronicalcoholism and had received treatment for aseizure disorder with anticonvulsants for severalyears. He had chronic lung disease and had beenhospitalized one year previously for a lungabscess. One week before the present admission hewas noted to have left arm weakness. Onadmission he was afebrile and stuporous, with



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CIF w. PERFUSIOM PRISSURE CBF vi. pCO,

FIGURE 6

The left graph relates the average rCBFtMtial in the frontal O region and the parietal Aregion to the perfusion pressure at each CBF study in case 3. It can be seen that in thefrontal area flow decreases as the perfusion pressure decreases. In the parietal area the flowincreases from CBF 1 to CBF 2 with decreasing perfusion pressure. From CBF 2 to CBF 4the flow decreases with decreasing perfusion pressure. The right graph relates the averagerCBFlnitlnl in the frontal O region and the parietal A region to the arterial Poo . The curveconnecting the solid circles O shows the normal COt reactivity curve from Reivich." It canbe seen that only in the parietal area from CBF I to CBF 2 does the rCBFinitial followthe normal COt reactivity curve. The remainder of the comparisons shows that the COt

reactivity is absent.

poor respiration and a left hemiparesis. Anangiogram showed a right posterior frontal massand a lumbar puncture showed elevated pressure,clear fluid, 500 polynuclear cells and 258 mg %protein. Through a perforator opening an abscesswas drained. The cavity was small and markedcerebritis was noted. Penicillin and Pantopaquewere placed in the abscess cavity. He was treatedwith systemic antibiotics and anticonvulsants. Thefollowing day he was more alert but thehemiparesis was unchanged. Over a period of dayshe became more obtunded and respiratory insuffi-ciency developed. The abscess cavity was repunc-tured and a brain scan showed a single lesion.Cultures produced no growth. A nasotracheal tubewas placed and respiratory assist with a volumerespirator was instituted. The following day, anepidural pressure transducer was placed in theright frontal area. Closed cannulation of the leftventricle was also performed for both pressuremonitoring and control. A catheter was placed inthe right internal carotid artery. Clinical examina-tion showed a comotose patient unable to followcommands. The pupils were equal and the ocularmovements were intact. A left central facial andleft arm paresis were present with lefthyperreflexia and Babinski response. At the firstCBF study, the MABP was 115 mm Hg and the


epidural pressure 78 mm Hg, resulting in a PP of37 mm Hg. The arterial PCOo was 27 mm Hg. Theaverage rCBFln was 14.5 ml/100 gm/min withthe decreased flow more marked in the posteriorfrontal region. The PP was increased to 95 mmHg by the removal of ventricular fluid, resultingin an increase in the average rCBF10 to 21.3ml/100 gm/min, the most marked increaseoccurring in the area with the largest focaldecrease. Even though an increase in flowoccurred with ventricular drainage, all valuesremained markedly low. The ventricular fluid wasclear and had 6 polynuclear cells/mm3 and 45mg % protein.

An angiogram following the flow studyshowed persistence of the mass effect and mildnarrowing of the vasculature consistent with aninfectious process.

The high intracranial pressure was treatedwith periodic intravenous administration ofmannitol and ventricular fluid drainage. Five dayslater the patient was awake; his respiratory statuswas improved but he still had a marked lefthemiplegia. A CBF study and angiogram wasagain performed. At the first CBF measurement atthis occasion the ICP was still elevated to 70 mmHg but the MABP had increased to 136 mm Hg,raising the PP to 66 mm Hg. The arterial PCOo

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was 19 mm Hg. The average rCBF10 was 17ml/100 gm/min with persistent focal decreases.Raising the PP to 110 mm Hg by removingventricular fluid resulted in an insignificantincrease in the average rCBF10 to 18 ml/100gm/min. An EEG the following day showedmarked slowing and depressed amplitude over thewhole right hemisphere. The patient continued tobecome more alert and was able to communicateand write. He was gradually taken from therespirator. The dense left hemiplegia persisted. Arepeat angiogram showed marked diminution of

the mass effect. He was discharged to a localhospital for rehabilitation.

CommentThis case illustrates the effect of PP as the braindisorder progresses from an acute to a chronicstage. This is shown in figure 7. The initial studyshowed markedly decreased flow in the wholeright hemisphere greatest in the area of theabscess. The low PP of 37 mm Hg was a factor inthe flow decrease, and increasing the PP byremoving ventricular fluid resulted in a marked

SL 3-71 CBF and PERFUSION PRESSURE

FLOW 1 FLOW 2

m*an1 *

14.3 mi/'

MABPICPPP

pCO,

111M

n»7

37

.1 " "

91 »

M

>• 30

meon31.3 t

MABPICPPP

pCO,

rCBF10

1 1 3 i

30

93

24

mean r CBF)0

Itml/toog/mln

Ai Aft ft I * A ••• U_

ICP 30PP 110

pCO. i»

/ » » 17 17 a*

' U 13 H « W

S0 2O W 3O ZS

rCBFMt

192

FIGURE 7

Case 4, illustrating the first and second CBF studies. In the lower right is the brain scanperformed one day after the first CBF study. Flow 1 shows the flow increase which occurswhen the PP is increased from 37 mm Hg to 95 mm Hg, particularly in ischemic focuscorrespondent to the abscess. Flow 2 shows that no significant flow increase occurs withaii increase of the PP from 66 mm Hg to 110 mm Hg.

Strok; Vol. 3, March-April 1972


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increase in flow. Five days later the situation hadchanged. During this period respiration wasassisted with a volume respirator and markedhypocapnia had been maintained. Although thepatient was awake and could follow simplecommands, he had a dense left hemiplegia. Byclinical examination one could estimate that thesigns associated with marked increased pressurehad subsided but that severe and possiblyirreversible right cerebral hemisphere damage waspresent. The EEG at that time showed markedslowing and depression over the right hemisphere.The ICP had decreased only slightly, to 70 mmHg. However, the MABP had increased to 136mm Hg resulting in a PP of 66 mm Hg. The CBFstudy confirmed the severe hemisphere involvementwith the flow still markedly decreased to 17ml/100 gm/min. The arterial Pco., was 19 mmHg. At this stage an increase in the PP to 110 mmHg by removing ventricular fluid resulted in nosignificant change in flow, demonstrating that nowautoregulation was present (at this low PQ0 O)-

DiscussionThe data on intracranial pressure, systemicarterial pressure and cerebral blood flow fromthe four described patients show very clearlythat concepts of the relationship of perfusionpressure to flow, that was demonstrated byZwetnow1- in his animal studies, can beapplicable to clinical situations. When theperfusion pressure falls below the normalautoregulatory range, by combinations ofeither intracranial pressure increases or sys-temic blood pressure decreases, both normaland damaged brain tissue reacts with a pressurepassive flow response. This finding of criticallylow perfusion pressure was found in all fourpatients, two of whom progressed to zeroperfusion pressure and cessation of flow.

With the perfusion pressure in the normalautoregulatory range, Zwetnow1* also demon-strated that when a state of hypercapnia existsthen the cerebral arterioles are dilated andreact passively to changes in perfusion pres-sure. This loss of autoregulation which occursat hypercapnia resembles the loss of autoregu-lation which is seen with various types of acutebrain injuries. This latter type of autoregula-tory impairment has been related to tissueacidosis. Case 3 shows this type of autoregula-tory loss in the damaged frontal area at thestage when the perfusion pressure is in anormal range. The observations in case 3 alsooffer an explanation for the paradoxical flow


decrease during an increase in PCo2 oftenfound in space-occupying lesions. In the frontalarea, the decrease in flow with an increase inPc0., was the result of the narrowing ofperfusion pressure presumably caused by anincrease in blood volume in the cranialcavity.

If one analyzes the relation of flow toperfusion pressure in all four patients (fig. 1),the flow values in the hypocapnic range followthe autoregulatory plateau. However, at nor-mocapnia all of the flow values are associatedwith perfusion pressures which are below theautoregulatory range. This finding of lowerperfusion pressures at normocapnia can also beexplained by a Pco.,-induced cerebral bloodvolume increase.

The described measurements of bloodpressure, intracranial pressure and perfusionpressure correlated to cerebral blood flow aretherapeutically important because they allowmore rational planning of techniques to controlintracranial pressure, whether it be by surgicaldecompression, ventricular drainage, dehydrat-ing agents or steroids.

It must be stressed that the presentdeterminations do not allow estimation ofadequacy of blood flow for cerebral tissueoxygenation. However, this may be provided inthe future by regional oxygen utilization by the]r'Oxygen method.34

The present method of measuring thecerebral perfusion pressure is open to criticismbecause it is based on the assumption that thepressures within the craniospinal enclosure areall equal.3fii 80 Weinstein et al.87 have shownthat local pressure-creating factors act withinlocal compartments and that single supraten-torial pressure measurements are not complete-ly relevant in a system which is not purelyhydrostatic. AH four cases suggest that this istrue in that the supratentorial hemisphericcirculatory impairment that was measuredcorrelated poorly with the clinical findings ofbrain stem dysfunction. Kaufman and Clark38

have demonstrated that the combination ofsupratentorial and cisterna magna pressuremeasurements can provide information aboutpressure gradients.

In conclusion, the relatively simple systemof determining cerebral perfusion pressure usedin this study of patients can be practicallyapplied in all clinical situations with increased

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intracranial pressure. However, it is only astart toward analysis of the complex effects ofpressure gradients within the craniospinalenclosure.

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M. PETER HEILBRUN, PAUL BALSLEV JORGENSEN and GUDRUN BOYSENPatients With Severe Neurological Disorders

Relationships Between Cerebral Perfusion Pressure and Regional Cerebral Blood Flow in

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