comparison of krypton and xenon cerebral blood flow ... filecomparison of 85krypton and 133 xenon...

Comparison of 85Krypton and 133Xenon Cerebral Blood FlowMeasurements before, during, and following Focal, Incomplete Ischemiain the Squirrel Monkey

By E. Jerome Hanson, Jr., Robert E. Anderson, and Thoralf M. Sundt, Jr.

ABSTRACTA comparison of regional cerebral blood flow measurements made with beta-

and gamma-emitting isotopes revealed good correspondence in areas of normalperfusion and reactive hyperemia but poor correspondence in areas of focalischemia. After middle cerebral artery occlusion at normocapnia, there was a65% reduction in regional cerebral blood flow from 1.40 ± 0.27 ml/g min~' to 0.49± 0.10 ml/g min~' in monkeys studied with 85Kr but only a 27% reduction inregional cerebral blood flow from 0.84 ± 0.09 ml/g min-' to 0.61 ± 0.08 ml/g min~'in monkeys studied with 133Xe. The lack of correlation within areas of focal,incomplete ischemia was attributed to an impairment of isotope delivery tothe area of ischemia coupled with the inherent lack of spatial resolution ofdeterminations made with 133Xe. This finding may partly explain the numerousdiscrepancies in experimental and clinical studies of the effects of alterationsin the arterial partial pressure of C(X on regional cerebral blood flow in areasof ischemia; it may also explain the failure of such studies to reflect the trueseverity of focal ischemia.

KEY WORDS cerebral autoregulationCompton's scatter steallook-through phenomenon

luxury perfusioncritical blood flow

reverse steal

• Clinical and laboratory investigators gen-erally agree that use of 133Xe provides goodcorrespondence and documentation for vari-ations in regional blood flow in the normalbrain caused by alterations in the level ofarterial carbon dioxide tension (PCO2) (1-4),"luxury perfusion" (5-8), and vasoparalysisin areas of ischemia with a loss of autoregu-lation (5-8). However, conflicting data havebeen reported for the severity of reduction in(4-6, 9) and the influence of altered arterialPCO2 on (4-6, 10) regional cerebral blood flowin areas of infarction.

The present study was undertaken in aproved model of focal, incomplete ischemia(11, 12) to determine if these discrepanciesare due to the lack of spatial resolution in-herent in techniques tha t depend on agamma emitter. Errors from the "look-through" phenomenon (6, 8) and Compton'sscatter (13-15) have been cited by knowledge-

From the Cerebrovascular Clinical Research Centerand the Department of Neurologic Surgery, Mayo Clinicand Mayo Foundation, Rochester, Minnesota 55901.

This investigation was supported in part by U. S.Public Health Service Grant NS-6663 from the NationalInstitutes of Health.

Received April 8, 1974. Accepted for publication Au-gust 27, 1974.

18

able workers in this field but have not beendocumented in laboratory models.

MethodsLABORATORY PREPARATION

The surgical technique, methodology of cerebralblood flow measurements, injection of indicatorsinto an isolated right internal carotid artery sys-tem, and recording of systemic parameters in thislaboratory preparation of focal, incomplete is-chemia in the squirrel monkey have been previ-ously described in detail (11, 12). In the presentstudy, the transorbital approach (16, 17) was sub-stituted for the retro-orbital approach. Twogroups of monkeys, anesthetized with sodiumpentobarbital (20 mg/kg, ip) and separated accord-ing to the indicator used to determine regionalcerebral blood flow, i.e., 85Kr or 133Xe, were stud-ied. In the 85Kr group, a right frontotemporoparie-tal craniectomy and dural resection allowed re-cordings to be made from a brain protected bySaran Wrap. In the I33Xe group, craniectomy wasunnecessary. Recordings in both groups werefrom identical right frontoparietal areas, and theprotocol for each experiment was identical in thetwo groups except for the indicator used. Determi-nations of regional cerebral blood flow were ob-tained at 20-minute intervals at variable levels ofarterial Pco., for 90 minutes prior to occlusion ofthe right middle cerebral artery, for 70 minutesduring occlusion, and for 30 minutes after releaseof occlusion (Figs. 1 and 2). Arterial PC(X wasvaried by altering the concentration of inspired

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CEREBRAL BLOOD FLOW IN FOCAL ISCHEMIA

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Measurements of regional cerebral blood flow (rCBF) obtainedwith ""Kr (solid line) and I33Xe (broken line) before, during,and after focal ischemia induced by temporary occlusion of themiddle cerebral artery (MCA) in the squirrel monkey ascalculated by kinetic analysis. Variations in flow are recordedbefore, during, and after ischemia with alterations in arterialcarbon dioxide tension (Par,,J and mean arterial blood pres-sure (MABP). Reduction in mean arterial blood pressure withhypocapnia in this preparation could have minimized a re-verse steal. During ischemia, the values obtained with l33Xedid not reflect the severity of flow reduction measured in themKr group. Regional cerebral blood flow continued to vary inresponse to alterations in arterial Pco2 in the l33Xe group butdid not change significantly throughout the period of ischemiain the ^Kr group. Failure to accurately reflect the significantreduction in regional cerebral blood flow during ischemia andthe persistence of CO2 responsivity in the monkeys studiedwith '33Xe is attributed to look-through phenomenon andCompton's scatter. Asterisk indicates mean values ± SE ob-tained during spontaneous respiration.

CO;,. The arterial partial pressure of 0., (Po.,) wasmaintained constant at 100-20 torr. Only mon-keys that demonstrated normal variations in re-gional cerebral blood flow from changes in arterialPCCX prior to right middle cerebral artery occlu-sion were included for final analysis of the is-chemic period (five monkeys with 85Kr and fivemonkeys with 133Xe; seven monkeys were ex-cluded). The volume of injectate for each regionalcerebral blood flow determination was 0.1 ml (100± 25 /iAc/ml of activity for 85Kr and 150 ± 50 p.dm\of activity for 133Xe). 85Kr was recorded by an


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uncollimated, argon-quenched Geiger-Miiller tubewith an end-window diameter of 6 mm. 133Xe wasrecorded by a single scintillation detector with athallium-activated sodium iodide crystal recessed2.5 cm behind a lead collimator shaped like aninverse cone, widening from an opening 0.93 cm indiameter at its face to one 1.875 cm in diameter atthe crystal surface.

REGIONAL CEREBRAL BLOOD FLOW DETERMINATIONS

Regional cerebral blood flow was determinedwith both indicators by a simplified method of theinitial slope technique (18) during the laboratoryprocedure and by the kinetic analysis of Zierler(19) after the experiment. The initial slope methodprimarily measures gray matter flow, whereas the

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Measurements of regional cerebral blood flow (rCBF) obtainedwith sKr (solid line) and l33Xe (broken line) before, during,and after focal ischemia induced by temporary occlusion of themiddle cerebral artery (MCA) in the squirrel monkey ascalculated by initial slope analysis. In this preparation, initialslope analysis correlated closely to the gray matter flow ofexponential analysis (r = 0.98). The artifact of the look-through phenomenon could not be eliminated by methods ofanalysis using only the fast component of the l33Xe washoutcurve. Asterisk indicates mean values ± SE obtained duringspontaneous respiration. See Figure 1 for definition of otherabbreviations.



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20 HANSON,ANDERSON, SUNDT

kinetic analysis also includes a contribution fromwhite matter. The more complex calculations in-volved in exponential analysis were not per-formed for two reasons. (1) Regional cerebralblood flow calculated by the initial slope formulacorrelates very closely with the value for graymatter flow obtained by exponential analysis (r =0.98) (18, 20) and (2) the relative contributions ofthe two components (gray matter [Wg] and whitematter [Ww]) derived from exponential analysisvary as much as 30% during successive injections,despite relatively constant systemic blood pres-sure and arterial PCCX levels (18). Correspondenceof changes was excellent between the two tech-niques (the values obtained by the initial slopetechnique were higher than those obtained bykinetic analysis in both groups of monkeys). Al-though regional cerebral blood flow measured byboth techniques is reported in the present paper,conclusions were based primarily on the dataobtained by the kinetic analysis, reflecting ourconfidence in the superior reliability of this tech-nique.

60

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FIGURE 3

Arterial partial pressure of C02-regional cerebral blood flowresponse curve for measurements of^Kr before middle cere-bral artery occlusion (solid line) indicated a normal-appear-ing curve (kinetic analysis). After middle cerebral arteryocclusion (broken line), there was a loss of autoregulationwith no significant change in regional cerebral blood flow(rCBF) in response to alterations in arterial carbon dioxidetension (Par,,J. Monkeys breathing spontaneously prior tocontrolled ventilation (open circle) were excluded from theplotted curve in this group. Values are means ± SE.

30 40 50 60

P a c o ( t o r r )FIGURE 4

Arterial partial pressure of CO2-regional cerebral blood flowresponse curve for measurements of'33Xe before middle cere-bral artery occlusion (solid line) indicated a normal-appear-ing curve (kinetic analysis). After middle cerebral arteryocclusion (broken line), measurements of regional cerebralblood flow (rCBF) continued to vary directly with alterationsin arterial carbon dioxide tension (PavllJ, indicating a failureof this indicator to reflect the true degree of ischemia in thearea immediately under the probe (look-through phenome-non). Monkeys breathing spontaneously prior to controlledventilation (open circle) were also excluded from the plottedcurve in this group (see Fig. 3). Values are means ± SE.

ARTERIAL PARTIAL PRESSURE OF CARBON DIOXIDE-REGIONALCEREBRAL BLOOD FLOW RESPONSE CURVE

The normal physiological response of cerebralblood flow to variations in arterial PCO2 was deter-mined for monkeys studied using 85Kr (Fig. 3) and133Xe (Fig. 4) prior to and after right middlecerebral artery occlusion. These curves were cre-ated from the mean values of regional cerebralblood flow determinations at 20, 30, 40, and 60 torrand represent 20 separate regional cerebral bloodflow determinations in each group. Regional cere-bral blood flow values in spontaneously breathingmonkeys (arterial PCCX,, 33 torr) were not includedin the curves. Only monkeys demonstrating aphysiological response to alterations in arterialPCO, and thereby representing reliable prepara-tions were included in this analysis (21).

CALIBRATION OF THE GEIGER-MULLER PROBE

Several unsuccessful attempts to calibrate theGeiger-Miiller probe with equipment available inour laboratory were made. In each case, calibra-tion could not be performed because a pointsource of beta particles with sufficient potency topenetrate the walls of the water beaker was notavailable. However, based on data provided by themanufacturer (Electronics, Optical, Nuclear Cor-poration) and the Department of Health, Educa-tion and Welfare (22), a figure of the field of view




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CEREBRAL BLOOD FLOW IN FOCAL ISCHEMIA 21

of the argon-quenched Geiger-Miiller tube wasconstructed. Only the activity coming from a dis-crete volume of tissue 2.5 mm in depth with sidescatter limited to approximately 1° is detected(Fig. 5). This depth is slightly greater than thatreported previously by other investigators (23-25),but it still corresponds closely to their results.

ISORESPONSE CURVE FOR ">X»

The isoresponse curve for the detection of thegamma photon of 133Xe by the detector used inthis study was determined (13). The detector wasplaced perpendicular to the 2-mm side wall of abeaker filled with water. A discrete point source of133Xe was placed directly in front of the probe inthe central portion of the field of view of theprobe, and the maximal counting rate was deter-mined. The point source was moved through thefield of view of the scintillation detector, and themaximal counting rate was determined at 5-mmintervals. The lower level discriminator was set at75 kev so that only the 81-kev photopeak and asmall portion of Compton's scatter was detected.This setting corresponds to that used during theexperimental procedure. Areas with relativelyequal levels of counts were then plotted, and anisoresponse curve was obtained (Fig. 6). The aver-age coronal diameter of the squirrel monkey brainunderlying the probe was 33.8 mm. The scalp,calvarium, and dura mater accounted for 3 mm ofthe distance between the face of the collimatorand the brain. The sagittal plane of the brain waslocated 22 mm from the opening of the collimator.Thus, the 50% line of the isoresponse curvepassed 3.0 mm across the sagittal plane into theleft cerebral hemisphere. However, a significantamount of indicator probably did not perfuse theleft hemisphere, and even if it did the error intro-duced would be similar only to that created by theactivity originating in the right parasagittal area

Isoresponse Curve

x Geiger-Miillertube

Limits ofmonkey skull

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Relative size of argon-quenched Geiger-Miiller tube used inthis experiment compared with a tracing of the monkey brain.Tube is shown at its normal location for recording.


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Isoresponse curve of 133Xe determined using a scintillationcounter is significantly different from the theoretical truncatedcone shown in Figure 7.

supplied by the right anterior cerebral artery tothe nonischemic tissue adjacent to the territory ofthe right middle cerebral artery.DETERMINATION OF COMPTON'S SCATTER

The total activity detected by the thallium-activated sodium iodide probe also containedCompton's scatter photons. To quantify the con-tribution of Compton's scatter to total activityand, hence, to more clearly define the physicallimits of anatomic resolution of the 133Xe tech-nique, a study was performed according to themethod of Potchen et al. (14, 15). A glass cylinderwith a glass cone inside that duplicated the theo-retical truncated cone was placed over the 133Xeprobe (Fig. 7). The cylinder outside the cone wasfilled with a saline solution of 133Xe (3 me 133Xe/125ml saline), and the activity was measured at 5-kevintervals from 25 kev to 120 kev with air in thecentral cone. This measurement representedbackground activity with negligible Compton'sscatter. The central cone was then filled withsaline to simulate Compton's scatter comparablewith that of tissue, and determinations of theactivity were repeated. Finally, the central conewas filled with saline containing the same concen-tration of 133Xe used in the exterior chamber, andthis activity was also determined. The contribu-tion of Compton's scatter was determined by sub-tracting the values obtained with air in the cen-tral cone from those obtained when water filledthe central cone. There was significant activitycontributed by Compton's scatter (Fig. 8). Therewas also a 13-kev shift in the peak activity de-tected when the central cone was filled withwater. A 75-kev lower window eliminated most ofthe activity contributed by Compton's scatter(Fig. 8). However, of the total activity above 75kev recorded in this model with both compart-ments filled with I33Xe, 12.5% was still due toCompton's scatter.



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22 HANSON, ANDERSON, SUNDT

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Theoretical truncated cone for recording "3Xe using the scin-tillation counter was significantly different from the actualisoresponse curve obtained (see Fig. 6).

ResultsSTABILITY AND RELIABILITY OF LABORATORY PREPARATION

Loss of blood during the entire experimen-tal procedure was less than 3 ml; transfusionof blood was never necessary. Based on therespiratory rate and the degree of sponta-neous movements, none of the monkeys in-cluded for final analysis was in an exces-sively deep plane of anesthesia. It was nevernecessary to supplement the original dose ofanesthetic. Serial hematocrit levels per-formed throughout the experiment demon-strated no hemodilution or evidence of signif-icant loss of blood. Core body temperaturewas maintained at 36.5°C throughout theexperiment by means previously describedfor this preparation (11, 12). Monkeys inwhich a physiologic response to alterationsin arterial PCO2 could not be demonstratedprior to occlusion of the middle cerebral ar-tery were excluded from the study. In thesepreparations, the cause of the impaired re-sponse was not always apparent. However,in two of the monkeys, it was considered tobe a secondary effect of the craniectomywithout gross evidence of cortical damage, intwo other monkeys, it was assumed thatminute amounts of air entered the injectingsystem used to deliver the radioactive indica-tor, and in three monkeys, transient hypo-tension and hypoxia occurred with curariza-tion and institution of mechanical ventila-tion.

REGIONAL CEREBRAL BLOOD FLOW DETERMINATIONS

Alterations in regional cerebral blood flowcaused by changes in arterial PCO2 before,during, and after occlusion of the middlecerebral artery are summarized for bothgroups by kinetic analysis (Fig. 1) and initialslope analysis (Fig. 2). Regardless of themethod of calculation, the degree of flowreduction measured with 85Kr far exceededthat measured with l33Xe during ischemia.Mean regional cerebral blood flow remainednearly constant throughout the period ofischemia despite alterations in arterial PCO2when 85Kr was used as the isotope by bothmethods of analysis, although values ob-tained with the initial slope technique werehigher than those obtained with kinetic anal-ysis. However, when 133Xe was used as theisotope, mean regional cerebral blood flowcontinued to vary directly with arterial PCO.,throughout the period of ischemia regardlessof the method of analysis (kinetic analysisrange 0.28 ± 0.04 ml/g min"1 to 0.83 ± 0.11 ml/g min"1, initial slope range 0.28 ± 0.05 ml/gmin"1 to 1.30 ± 0.21 ml/g min"'). Examinationof individual arterial PCO2-regional cerebralblood flow response curves during ischemiain the 85Kr group revealed one monkey with adefinite increase in flow during hypercapnia(0.63 ml/g min"1 to 0.82 ml/g min~', arterialPCO., 25 torr to 56 torr, and mean arterial

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Determination of Compton's scatter using the scintillationcounter employed for measurements of'33Xe in the monkeysindicated a significant contribution from Compton's scatterthat could not be excluded.




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blood pressure 107 mm Hg to 119 mm Hg)and one monkey with an increase in flow inresponse to hypocapnia (0.65 ml/g min~' to0.90 ml/g min"1, arterial PCO._, 36 torr to 24torr, mean arterial blood pressure 105 mmHg to 99 mm Hg). These two monkeys werethe only ones in the 85Kr group in whichregional cerebral blood flow changed signifi-cantly in response to alterations in arterialPCO2 during the period of ischemia. Thechanges in regional cerebral blood flow meas-ured in the first monkey could have beensecondary to increased perfusion pressure,and those in the second monkey might repre-sent an "inverse steal" syndrome. We attrib-ute the apparent continued physiological re-sponse to alterations in arterial PCO2 duringischemia as measured with l33Xe to the look-through phenomenon. This inherent lack ofspatial resolution of l33Xe-regional cerebralblood flow studies may explain previous ob-servations of increased flow within focalareas of ischemia in response to hypercapnia(4, 10).

ARTERIAL PARTIAL PRESSURE OF CARBON DIOXIDE-REGIONALCEREBRAL BLOOD FLOW RESPONSE CURVES

The shapes of the arterial Pco.2-regionalcerebral blood flow response curves (kineticanalysis) for studies performed using 85Krand l33Xe were similar prior to middle cere-bral artery occlusion (solid lines, Figs. 3 and4); the higher flows measured with 85Kr re-flect essentially gray matter flow. Duringischemia (broken lines, Figs. 3 and 4), therewas no significant change in regional cere-bral blood flow in response to alterations inarterial PCO2 in monkeys studied with 85Kr,whereas a direct positive correlation wasfound in monkeys in which IMXe was used asthe isotope (values obtained by kinetic anal-ysis showed less change than values ob-tained by the initial slope technique). Forreasons not clear to us, routinely there was amodest increase in regional cerebral bloodflow when monkeys were placed on con-trolled ventilation compared with base-linelevels obtained with monkeys breathingspontaneously at the same level of arterialPCO,.

DiscussionCOMPARISON OF BETA AND GAMMA MEASUREMENTS

The Geiger-Miiller probe recorded betaparticles originating from very superficialCirculation Research, Vol. 36, January 1975

layers of the brain and did not detect signifi-cant activity from a clsp'tri greater than 2.5mm. This situation is consistent with data onthe characteristics of the indicator that areaccepted by most workers in the field (23-25).As previously indicated, counts were re-corded through Saran Wrap, since the durain this preparation has been demonstrated torepresent a significant barrier to this indica-tor (Fig. 5) (11, 24).

Examination of the theoretical truncatedcone (Fig. 7), the measu-red isoresponse curve(Fig. 6) for the detection, of gamma activity,and the information relative to possible con-tamination from Compton's scatter (Fig. 8)indicates the potential error introduced bythe lack of spatial resolution for a gamma-emitting indicator. Figures 1 and 2 demon-strate the inability of regional cerebral bloodflow determinations with" 133Xe, using the in-strumentation of the present study, to accu-rately reflect the severity of blood flow re-duction in regions of very severe ischemiaregardless of the method used to calculateregional cerebral blood flow. This findingconfirms previous observations by Paulsonand co-workers (13) on problems related tothe look-through phenomenon.

ARTERIAL PARTIAL PRESSURE OF CARBON DIOXIDE-REGIONALCEREBRAL BLOOD FLOW RESPONSE CURVES

The predictable shape of the arterial PCO2-regional cerebral blood flow response curvesfor monkeys studied with 85Kr and 133Xe indi-cated the reliability of these measurementsin nonischemic brain prior to occlusion of themiddle cerebral artery. The measurements ofeach preparation's response to alterations inarterial PCO2 prior to occlusion of the middlecerebral artery and the exclusion from studythereafter of all monkeys failing to demon-strate a normal autoxegulatory response en-sured that these experiments were per-formed in reliable laboiatory preparations.Lassen (21), Ingvar and Lassen (26), andothers (27-29) have previously stressed theimportance of such precautions in both labo-ratory and clinical studies.

"Kr AND ">X» MEASUREMENTS OF CEREBRAL BLOOD FLOW

There was good correspondence betweenthe two groups of motikeys during intervalsin which there was no obstruction or impair-ment of the delivery of indicator into theregion predestined for ischemia. Alterationsin regional cerebral blood flow caused by



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changes in arterial PCO2 prior to occlusion ofthe middle cerebral artery and luxury perfu-sion (reactive hyperemia) were of similarmagnitudes in both groups of monkeys. How-ever, during ischemia, when the relativeamount of indicator delivered to the areadirectly under the probe was markedly re-duced, a significant artifact arose in the 1MXegroup from lack of spatial resolution. To de-tect the true reduction of flow in a focal areaof ischemia using a gamma emitter, the con-centration of indicator in the region to bemeasured must be equal to that in the un-derlying and adjacent areas. When regionalcerebral blood flow measurements are per-formed during carotid endarterectomy, theindicator is delivered to the brain prior tocarotid artery occlusion, and the relative re-duction of flow is accurate unless there hasbeen an intracranial occlusion to prevent theindicator from arriving in the area to bemeasured (30-32). However, with an intra-cranial occlusion, such as that which resultsfrom an embolus, before the injection ofl33Xe, a representative amount of mXe maynot arrive in the area of focal ischemia, andcounts arriving under the probe may origi-nate from deeper or adjacent tissue and con-tribute to the clearance curve measured bythe probe (6, 8, 32).

Multiple small probes may partly reducethis artifact, and the probes can be colli-mated so that they record from a relativelysmall volume of tissue (9, 10, 13). Collimationmay narrow the theoretical cone of tissuewithin the field of view of the detector, butdepth resolution remains a function of thelinear absorption coefficient for the gammaphoton of 13:iXe. Problems related to Comp-ton's scatter also may result (13-15), andthey are especially important for gammaphotons whose energy is below 1.0 mev (33).Compton's scatter involves the interactionbetween an incident photon and an orbitalelectron in which only a part of the energy ofthe photon is imparted to the electron (34).The photon emerges from the interactionwith a new direction and reduced energy(34). The effect of Compton's scatter on thecounts detected using l33Xe can be approxi-mated in phantom studies (13-15). Dependingon the characteristics of the scintillation de-tectors and the photopeaks measured, stud-ies reported previously have shown that be-tween 35% (13) and 55% (14) of the total

activity seen by the probe may not comefrom tissue within the truncated cone under-lying the probe. Compton's scatter in effectincreases the volume of tissue from whichgamma photons are counted and may intro-duce a considerable error in the determina-tions of the volume and the severity of focalischemia. These factors introduced a majorerror in measurements of regional cerebralblood flow in a patient with acute occlusionof the middle cerebral artery from a cardiacsource prior to intracranial embolectomy(32).

CRITICAL CE REBRAL BLOOD FLOW

There is excellent correlation between thework of Boysen (30) and that of Sundt and co-workers (32) relating to continuous elec-troencephalograms and cerebral blood flowmeasurements during carotid endarterec-tomy. A. cerebral blood flow of 18 ml/100 gmin"3 is required to sustain a normal elec-troencephalogram for short periods (32, 35);this value agrees with that required formaintenance of normal carbohydrate metab-olism (36). Invariably, flow reductions belowthis level produce evidence of cerebral is-chemia as shown by changes in the elec-troencephalogram (32). These measurementsare free of the artifacts of the look-throughphenomenon as previously discussed, be-cause the indicator is delivered to the brainand the artery is occluded in the neck onlyafter counts are identified. Therefore, trueregional cerebral blood flow is reflected. Onoccasion, values as low as 5 ml/100 g min~'have been found during carotid occlusion(prior to placing a shunt); such values aremueh lower than those reported in most clin-ical studies in patients with infarction (4-6,8, 37, 38). Our measurements were performedunder halothane anesthesia with a moderatedegree of induced hypertension; neverthe-less, they reflect the amazing ability of thebrain to compensate for severe reductions inflow up to a point of critical perfusion. Com-parison of these critical levels of flow withregions of focal ischemia found in clinicalstudies using 133Xe in patients with acuteand chronic infarctions (4-6, 8, 37, 38) indi-cates the significant possibility that the trueseverity of regional flow impairment has notbeen identified because of the problems ofthe look-through phenomenon and Comp-ton's scatter. This possibility does not mini-




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mize the importance of such investigations,but it does indicate the necessity of under-standing the possible contribution of countsfrom underlying or adjacent perfused tissue.The more sophisticated instrumentation andtechniques for measurement currently underdevelopment in which the relative number ofcounts is also considered may partly circum-vent this obstacle.STEAL AND REVERSE STEAL

The failure to more clearly document stealand reverse steal in our laboratory prepara-tion does not indicate that they do not occur.Waltz (29) has previously suggested that theparadoxical response to hypercapnia (intra-cerebral steal) is related to the volume oftissue involved, the severity of ischemia, andthe time delay between the ischemic episodeand regional cerebral blood flow mea-surement (39). Previously, it has been demon-strated (40) that the squirrel monkey has alarge area of infarction after permanent oc-clusion of the middle cerebral artery. In ani-mals with a lesser degree of ischemia such asthe cat, these paradoxical responses to hy-percapnia have been documented (29). Inother experimental preparations with rela-tively smaller areas of ischemia, some inves-tigators (10, 41, 42) have demonstrated byother techniques of cerebral blood flow mea-surement an increase in cerebral blood flowafter an increase in arterial PCO2. The inabil-ity to demonstrate more commonly the para-doxical responses to hypercapnia and hypo-capnia in clinical situations is probably inex-tricably related to the limitations of spatialresolution imposed by the use of a gammaindicator and to the temporal relationship ofthe onset of the ischemic deficit and theregional cerebral blood flow measurement.Autoradiographic measurements (43) haveindicated the profound variability of flowwithin discrete regions in and adjacent tothe area of ischemia; these variations rangefrom 3 ml/100 g min"' in the core area ofinfarction to more than 100 ml/100 g min"1 inmarginal zones of hyperemia (44). It is un-likely that this flow pattern in ischemicareas will be accurately detected by currenttechniques of external counting.

AcknowledgmentThe authors gratefully acknowledge the technical as-

sistance provided by Mr. Donald Lilja and the secretarialassistance of Ms. Ethel G. DeSerre.Circulation Research, Vol. 36, January 1975

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E J Hanson, R E Anderson and T M Sund, Jrand following focal, incomplete ischemia in the squirrel monkey.

Comparison of 85krypton and 133xenon cerebral blood flow measurements before, during,

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