Regional Cerebral Blood Flow and Focal Cortical ... - SAGE Journals

Journal o/Cerebral Blood Flow and Metabolism 7:207-213 © 1987 Raven Press, New York

Regional Cerebral Blood Flow and Focal Cortical Perfusion: A Comparative Study of 133Xe, 85Kr, and U mbelliferone as Diffusible Indicators

Robert E. Anders on, Thoralf M. Sundt, Jr., and Tony L. Yaksh Cerebrovascular Research Center and the Department of Neurologic Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, U.S.A.

Summary: We report that regional CBF determined by

steep by 56% and 45% , respectively. U mbelliferone, measuring a much smaller volume of tissue, showed a lower normocapnic flow and a more oblique Paco2 re sponse curve. In the rabbits studied, the normocarbic rCBFs and the rCBF- Paco2 response curves measured with the three techniques corresponded to those mea sured in the cat. These results suggest that large field/ volume measurements assess a measure of flow that is a weighted average of several distinct flow compartments and that these compartments differ in their response to changes in PaC02' Key Words: Focal cortical perfusion Paco2 reactivity-rCBF.

the initial slope technique using 133Xe and 85Kr in cats and rabbits can be significantly influenced by the siz e of the field of measurement. The clearance curves of umbel liferone, a lipid-soluble intracellular pH fluorescent indi cator, from a visually avascular 80-f-I,m field were used to cross-correlate rCBF with focal cortical perfusion. Our findings indicate that in the cat, as the gamma or beta detector's field of volume was reduced, regional CBF (rCBF) measured by intraarterially injected 133Xe or 85Kr decreased in value by 33% and 28% , respectively, and the slope of the rCBF- PaC02 response curve became less

MATERIALS AND METHODS

In 1945, Kety and Schmidt developed an inert gas technique using nitrous oxide that permitted accu rate determinations of cerebral blood flow in humans. They reported blood flow values per 100 g of tissue in the brain. Their method has withstood the test of time and is considered the gold standard for total cerebral blood flow. In the ensuing 40 years, a vast number of other techniques have been developed to measure cerebral blood flow in a va riety of clinical and laboratory settings in both humans and laboratory animals. Reported rCBF values and rCBF -Paco2 response curves have varied a great deal from one laboratory to another, even though there are some general correlations among these studies. T he present work was under taken to help explain these discrepancies and to in troduce the concept of focal cortical perfusion using umbelliferone, a lipid-soluble pH-sensitive fluorescent indicator.

Experimental animals

Regional cortical blood flow was determined with mXe in 8 cats and 5 rabbits, with 85Kr in 5 cats and 10 rabbits, and with focal cortical perfusion with umbelliferone in 10 cats and 10 rabbits. All of these animals weighed between 2.5 and 3.5 kg to aid in analyz ing the effects of measure ment geometry in the cortex on clearance curves. It was not technically possible to record all three indicators si multaneously over the same area of cortex because of the differences in instrumentation techniques. Instrumenta tion for the detection of 133Xe, a gamma emitter, cannot be used for the detection of 85Kr, a beta emitter, or vice versa. Neither of these two counting systems can be used simultaneously with the umbelliferone technique, as they would interfere with the optical field of view. Therefore, all experiments were done identically in each of the six groups. The three indicators and the method of measure ment of each will be discussed separately below. Animal Preparation

All animals were induced with 4% halothane and main tained under 1.5% halothane for the surgical preparation; the anesthetic was lightened to 0.8% halothane for cor tical flow measurements. Catheters were inserted into the right femoral artery and vein for monitoring of blood pressure, sampling of arterial gases, and for the adminis tration of drugs. Each had placement of an endotracheal

Received July 24, 1986; accepted December 1, 1986. Address all correspondence and reprint request to Robert E. Anderson at Rm 5-224, East Joseph, St. Marys Hospital, Roch ester, MN 55902 U.S. A.

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R. E. ANDERSON ET AL.

tube, was given 0.15 mg/kg pancuronium bromide to eliminate respiratory efforts, and was maintained on a Harvard respirator. A PE-50 catheter was inserted into the right lingual artery so that its tip lay in the carotid artery for the injection of the diffusible indicators. In all of the animals, the skin, subcutaneous tissue, and muscles were excised over the right parietal area with a scalpel and with the aid of bipolar forceps. Blood loss never exceeded 5 ml. U sing a high-speed air drill, a uni lateral craniectomy was performed over the right parietal area in those animals studied with 85Kr and umbel liferone. A bilateral craniectomy was made for animals studied with 133Xe. Bone wax was then placed in the margins of the craniectomy. After removal of the dura with the aid of an Olympus operating microscope, a thin piece of Saran Wrap was placed on the cortex to prevent surface oxygenation. Arterial blood pressure was measured by a strain gauge attached to the femoral artery catheter and was displayed on a Grass model 78 polygraph. Core body temperature was monitored with a rectal digital thermometer, and the animals were kept normothermic by the use of a heating pad. With each measurement of a clearance curve, arte rial Paco2, PaOZ, and pH determinations were taken with a Radiometer digital blood gas analyzer. Arterial carbon dioxide tensions were altered by varying the amount of inspired carbon dioxide, and measurements of 40, 20, 60, and 40 mm Hg were repeated at values of Paco2• Xenon cerebral blood flow measurements

Regional CBF was measured by the clearance of a 0.5ml bolus of 0.9% saline containing 250 /-LCi of 133Xe. Two counting detector systems were used. One of them was a thallium-activated sodium iodide scintillation detector for the larger field of view, which was placed over the left parietal area in eight cats. This detector has a lead colli mator with a lO-mm internal diameter; its isoresponse curve, using water as an absorbing medium, is depicted in Fig. lAo The detector measures a volume of 74 mm3 at the 90% isoresponse level. This detector was not used in rabbits because it was physically too large (26 mm out-

side diameter) . The second detector used in the same group for simultaneous rCBF measurements was a solid state CdTe (cadmium telluride) device for the smaller field of view (1.5 mm) , with a counting volume of 5 mm3 at its 90% isoresponse level, which was also determined in an HP medium. In the eight cats studied, the rete mir abalis allowed an apportionate amount of 133Xe injectate to the opposite side studied, allowing simultaneous mea surements. In addition, five rabbits were studied using this solid-state detector placed over the right parietal area. The isoresponse curve for this detector is shown in Fig. IB (cats) and C (rabbits) . The lower level discrimi nator in the pulse height analyzer of both systems was set to 75-keV, so that only the 81-keV photopeak and a small portion of Compton's scatter was detected (Potchen et aI., 1967; Hanson et aI., 1975) . The time constant for the recording system was I S. Krypton cerebral blood flow measurements

Regional CBF was measured by the clearance of a 0.5ml bolus of 0.9% saline containing 200 /-LCi of 85Kr. An argon-quenched Geiger-Muller tube was used for re cording. A dual collimation system was constructed so one could select a field of either 6 mm (28 mm3 volume) or 1.5 mm (8 mm3 volume) in diameter. The 1.5-mm diam eter collimator was chosen as the minimum diameter for a statistically accepted count rate. Based on manufac turer's data (EON) , a figure of the field of view was con structed (Fig. 2A and B). Only the activity coming from a discrete volume of tissue, less than 1.0 mm in depth with side scatter limited to less than 10, is detected (Lassen and Ingvar, 1961) . Five cats were studied using both fields of view. The flow measurements were done in a sequential fashion, i.e., 6 mm, then 1.5 mm. In addition, 5 rabbits were studied using only the 1.5-mm field of view. The recording time constant was 1 S. Focal cortical perfusion measurements

Focal cortical perfusion was measured using umbel liferone, a lipid-soluble pH-sensitive fluorescent indicator that is used for the measurement of intracellular brain pH. The basic technology and instrumentation has been described previously (Sundt and Anderson, 1980b) . This indicator, 7-hydroxycoumarin, is nontoxic, fat soluble, and freely diffusible across the blood- brain barrier (Sundt and Anderson, I 980a) . The excitation and emission wavelengths used were 340 nm and 450 nm, respectively. This excitation wavelength of the dye is isobestic, and thus, the acidic and anionic forms are at an equilibrium.

Cat

Cat FIG. 1. The isoresponse curves depicted in their anatomical relationship to the cat (left) and rabbit (right) cortex for 133Xe.

(Al

and

Thallium-activated sodium iodide scintillation detector (8) solid-state CdTe detector.

J Cereb Blood Flow Me/ab, Vol. 7, No.2, 1987

Rabbit

FIG. 2. The field of view for the Geiger-Muller tube on the cat (left) and rabbit (right) cortex for either the 6-mm diameter (large circle) collimator or 1.5-mm diameter (small circle) collimator. The field of view for the umbelliferone fluores cent technique in both animals is represented by the dot.

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FOCAL CORTICAL PERFUSION AND rCEF Accordingly, the changes in fluorescent intensity are due only to changes in dye concentration. A typical fluores cent clearance curve is depicted in Fig. 3; point A repre sents the avascular spike and point B represents the en trance point of the indicator from the vascular space into brain tissue. The field of view in these experiments was 80 fL, as depicted in Fig. 2. The depth of tissue being re corded is 500 fL, as measured by Chance et ai. (1962) . The volume of tissue being measured is 0.003 mm3• Ten an imals of each specie were studied. Calculation of clearance curves

The initial-slope formula (Olesen et ai., 1971; Waltz et ai., 1972) was used to calculate the washout curves from each of the diffusible indicators used. The principal idea involved in the initial-slope method is that blood flow in the cerebral grey matter dominates the first part of the initial fall period (1- 2 min) of the clearance curve. The initial-slope values are to be considered as an approxima tion, that being the weighted average flow representative of the various tissue levels of grey matter. These layers consist of the pia layer, which could be considered as negligible, and the cortical layers, which have varying levels of capillary density that could have different rates of perfusion according to neuronal function (Lassen, 1965) . The more complex calculations involving biexponen tial analysis were not used because at hypocapnic and hypercapnic levels of PaC02, the bimodal propagation of rate constants of the clearance curve are not present (Reivich et ai., 1969b; Reivich, 1969) . In spite of their ana tomic distribution, grey matter flow can be identical to white matter flow in some regions, or vice versa (Battis tini et ai., 1969; Yamaguchi et ai., 1971) , under different physiological conditions because of their different rates of perfusion. The effects of arterial recirculation of 133Xe and 85Kr on clearance curves are minimal and have been well docu mented (Ingvar and Lassen, 1962; H¢edt-Rasmussen et ai., 1966; H¢edt-Rasmussen, 1967) . The effect of recircu lation of umbelliferone was assessed by (1) viewing the fluorescence of the dye passing through the surface vessels after injection, and (2) measurement of the arte rial concentration of umbelliferone by spectrophotometry after injection and subsequent washout. There was no re sidual fluorescence of the dye after the first pass in the cortical arterial tree, and the arterial concentration was found to be less than 1% .

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The partition coefficient (lambda) used for 133Xe was 0. 87 (Ingvar and Lassen, 1962) in cats and 0. 63 (Andersen and Ladefoged, 1967) in rabbits. Variations in fatty acid content between the two species may account for the dif ferences in these coefficients (Andersen and Ladefoged, 1967) . For the 85Kr clearance curves, lambda was 0.9 for both cats and rabbits (Lassen and Ingvar, 1961) . The par tition coefficient for umbelliferone was determined by giving a continuous intravenous infusion in an animal for 1 h. The animal was then killed, a blood sample taken from the heart, and the brain immediately removed. The samples were weighed and dried prior to nitric acid di gesting. The ratio between blood and brain (grey matter) was determined by measuring the extinction coefficient of each sample by a spectrophotometer at 340 nm, the peak wavelength of umbelliferone absorption. The parti tion coefficient for umbelliferone was determined to be 1. Statistical analysis

The significance of each measurement of clearance rate was determined by the Student's t test, paired and un paired samples. The deviation from the mean values is expressed as standard error.

RESULTS Xenon cerebral blood flow measurements

The 8 cats studied using the large field detector showed an rCBF-Paco2 response of 2.7 ± 0.4 mIlIOO g/min/mm Hg-Pacoz, with a mean flow of 56.9 ± 4.9 mIlIOO g/min at normocarbia. Using the small field detector simultaneously over the oppo site hemisphere, the slope of the rCBF response curve and the mean flow decreased significantly (p < 0.005) to 1.2 ± 0.2 ml/IOO g/min/mm Hg-Pacoz and 38.1 ± 3.1 mIlIOO g/min, respectively (Table 1 and Fig. 4A). Five rabbits were studied using the small field detector. T hese showed a slope of 0.8 ± 0.09 mlllOO g/min/mm Hg-Pacoz and a mean flow of 57.4 ± 3.2 mllIOO g/min (depicted in Table 2 and Fig. 4B). Although the rCBF-Paco2 response was not significantly different in the 8 cats using the small field detector, the mean flow value was signif icantly different (p < 0.005).

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TABLE 1. Comparison of mean flow and PaGo] responsiveness with /33Xe, 85Kr, and umbelliferone in the cat using large and small field of view detectors

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Krypton cerebral blood flow measurements

Five cats showed an rCBF-Paco2 response of 2.2 0.3 mlil00 g/min/mm Hg-Paco2, with a mean flow of 91.2 ± S.3 ml/100 g/min at normocarbia using the 6-mm field of view detector. This same group of cats, using the I.S-mm field of view de tector, showed a slope of 1.6 ± 0.4 ml/100 g/minl mm Hg-Paco2 and a mean flow of 67.S ± 7.9 at normocarbia. Although the Paco2-rCBF response was not significantly different, the mean flow was significantly different (p < O.OOS) in the five cats studied using the 6-mm field of view detector (Table 1 and Fig. SA). A mean flow of 76.6 ± 3.8 ml/l00 g/min at nor mocarbia was found, along with a slope of 1.2 ± 0.1 ml/l00 g/min/mm Hg-Paco2 in 10 rabbits using the 1.S-mm field of view. The mean flow and the Paco2-rCBF response (Table 2 and Fig. SB) was not significantly different from that in the S cats studied using the 1.S-mm field of view detector. ±

Paco2-focal cortical perfusion response curve was 0.74 ± 0.2 ml/100 g/min/mm Hg-Paco2 (Table 1 and Fig. 6A). The mean flow at normocarbia in 10 rabbits studied was 48.8 ± 3.2 ml/100 g/min, and the slope of the Paco2 response curve was 0.8 ± 0.2 ml/100 g/min/mm Hg-Paco2 (Table 2 and Fig. 6B). There were no significant differences in the slopes of the Paco2-focal cortical perfusion response curves or the mean flow at normocarbia between these two species. DISCUSSION

In order to place the term and concept of focal cortical perfusion and its relevancy to field of mea surement in perspective, it is necessary to review basic principles and current methods of CBF anal ysis.

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In 10 cats studied, the mean flow was 46.S ± 2.7 mlilOO g/min at normocarbia. The slope of the TABLE 2. Comparison of mean flow and PaCOZ responsiveness with 133Xe, 85Kr, and umbelliferone using the small field of view detector in the rabbit Indicator

Mean

Slope

133Xe 85Kr Umbelliferone

57.4 ± 3.2 76.6 ± 3.8 48.8 ± 3.2

0.8 ± 0.1 1.2 ± 0.1 0.8 ± 0.2

Mean flow = mlllOO g/min at normocapnia. Slope = mlllOO g/min/mm Hg-Paco2.

Vol. 7, No.2, 1987

Rabbit

Cat

Focal cortical perfusion

J Cereb Blood Flow Metab,

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FOCAL CORTICAL PERFUSION AND reBF Basic principles and assumptions

Velocity of flow through the arteries and arte rioles in any region of the brain is directly related to the number of functional capillaries in the field. With increased blood flow, the number of func tional capillaries increases (capillary recruitment). The transcapillary diffusion rate of the indicator is dependent on (A) the velocity of the indicator trav eling through the capillaries and (B) the solubility of the indicator in the capillary wall. Kety (1951) applied the Fick principle (Fick, 1870) and developed equations for measurement of regional blood flow with the following assumptions: (A) there is an instantaneous equilibrium of diffu sible indicator between blood and tissue, (B) there are no arterial-venous shunts present, (C) the dif fusible indicator is not metabolized by the tissue, and (D) the region of brain is homogeneous in reference to flow along with solubility of the indi cator. Kety (1951) indicated that for the inter capillary distances in the brain, equilibrium with blood would be nearly complete within 1 s, as suming that within the system, the solubility of the indicator is uniform. Kety (1949, 1951) also intro duced the factor"m," which is defined as the ef fectiveness of equilibration between blood and tissue during a single passage of the indicator through the capillaries. Combining the factor "m" with that of the partition coefficient lambda (A.), he substituted the tissue concentration for venous out flow concentration, and thus, made it possible to adapt his equations for external detection methods of CBF. However, because "m" was mathemati cally difficult to handle, it was later omitted by sev eral investigators who established their own algo rithms for calculating rCBF (Tomita and Gotoh, 1981). Comparison of methodologies

(1) Venous outflow. Reivich (1964), in a classic study using a thermistor flow meter to measure the venous outflow, showed a Paco2-rCBF response of 1.1 mlllOO g/min/mm Hg-Paco2 in primates, with a mean normocapnia blood flow of 49.3 mlllOO g/min. The mean flow is presumably lower than in the rat because of different metabolic demands (Eklof et aI., 1973). (2) Radioactive diffusible indicators. Eckman et aI. (1975) showed that when compared to 131J-tri fluoriodomethane, 14C-antipyrine was diffusion lim ited. This was related to capillary permeability being less at the higher flow rates. They concluded that the uptake of 14C-antipyrine in normal cat brain is limited by capillary diffusion as well as blood flow.

211

Eklof et al. (1974), using the method of Reivich (1969a), showed that 14C-antipyrine was severely diffusion limited at flow rates greater than 90 mlllOO g/min when compared to the Kety and Schmidt technique using 133Xe inhalation in the rat. They showed an rCBF-Paco2 response of 5.2 and 1.3 mlllOO g/min/mm Hg-Paco2 for 133Xe inhalation and 14C-antipyrine, respectively. The mean blood flow at normocapnia was 95 ± 5 for the 14C-anti pyrine and 100 ± 3 for the 133Xe inhalation, which are not significantly different. Alexander et aI. (1964), using 85Kr inhalation and a modification of the method of Lassen and Munck (1955) with arterial-jugular venous sampling deter mined that the CBF-Paco2 response was 1.37 mlllOO g/min/mm Hg-Paco2. They also reported a normocapnic blood flow of 49.7 mlllOO g/min in humans. McHenry et aI. (1965) found similar re sults in humans using the same technique. These findings correlated quite well with those previously reported by Kety. de Valois and de Groot (1975) did an analytical study of 85Kr, 133Xe, and 14C-antipyrine using Vi quidil, a vasodilating substance in rabbits. They found rCBF to be 48.3, 204.0, and 132.6 mllIOO g/min for 85Kr, 133Xe, and 14C-antipyrine, respec tively. They could not satisfactorily explain these differences. It can be postulated that one or two of these indicators is diffusion limited, and/or the method of computing rCBF was not the same in these indicators. (3) Radioactive nondiffusible indicators. Using radiolabeled microspheres in cats, AIm and Bill (1973) showed a normocapnic flow of 45 mllIOO g/min, with a Paco2 response of 7.5 mlllOO g/minl mm Hg-Paco2. This is obviously a nondiffusible in dicator technique, and changes in flow reflect only flow through the arterioles, perfused capillaries, and the volume of tissue measured. At high flow rates, these findings can be erroneous due to flow streaming through vessels (Neutze et aI. , 1968). (4) Nonradioactive diffusible indicators. Argon-methane. Ohta and Farhi (1979), using a double-tracer technique (argon and methane, which have similar partition coefficients), found a CBF Paco2 response curve similar to that of Harper and Glass (1965) of 1.2 mlllOO g/min/mm Hg-Paco2. Hydrogen. T he hydrogen clearance technique used by a number of investigators is reported to have shown widely varying values between species because of differences in analytical techniques. The relative shortcoming of this technique can be attrib uted to the fact that the flow compartment of its polyexponential clearance curve cannot be well de fined. This will not be discussed; the reader is reJ Cereb Blood Flow

Metab, Vol. 7, No.2, 1987


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ferred to a review article by Young (1980). How ever, it is important to note the work of Leniger Follert (1975), which showed that the value of rCBF can be influenced by the number of capil laries in the field of the hydrogen electrode. She demonstrated no significant changes with varia tions in PaC02 in the rat using a 15-J..Lm electrode, but found significant changes using a 100-J..Lm elec trode. Umbelliferone. This study indicates that umbel liferone can be used as an indicator for the mea surement of focal cortical perfusion. The clearance of umbelliferone is monoexponential, like that of 85Kr and the initial part of the clearance curve of 133Xe. The umbelliferone technique minimizes con tributions from larger vessels, which tend to in crease the mean flow as well as the slope of the Paco2 response curve, and thus approximates con ceptually Kety's original method, as the clearance curves are based on tissue saturation of the indi cator. Cerebral blood flow versus focal cortical perfusion

The principal assumption in these measurements is the homogeneity of the tissue from which the clearance of the indicator is assessed. The results of this study suggest that large field/volume mea surements assess a measure of flow that is a weighted average of several distinct flow compart ments (grey/white matter, arteries, arterioles, capil laries, and thoroughfare channels). Important are the differences and characteristics of the weighted responses of these heterogeneous compartments to changes in arterial Paco2. A distinction between rCBF, as measured by radiolabeled compounds, and focal cortical perfusion, as measured by the umbelliferone technique, can be made. Regional CBF is defined as the blood flow in local areas of tissue that contain arterioles as well as capillaries. Focal cortical perfusion can be defined as the blood flow through regions that are relatively avascular and contain only capillaries. Acknowledgment. The authors are indebted to Dr. Sey mour S. Kety for his constructive criticism and helpful suggestions. We are also grateful to Ms. Bernita Bruns for her preparation of the manuscript. This work was supported in part by National Institute of Health Grant NS-6663B.

REFERENCES

Andersen AM, Ladefoged J (1967) Partition coefficient of 133Xe between tissues and blood in vivo. ScandJ Clin Lab Invest

19:72-78 Battistini M, Casacchia M, Bartolini A, et al. (1969) Effects of hyperventilation on focal brain damage following middle ce rebral artery occlusion. In: Cerebral Blood Flow: Clinical andExperimental Results (Brock M, Fieschi C, Ingvar DH, et aI. , eds), Berlin, Springer-Verlag, pp 249-253 Chance B, Cohen P, Jobsis F, Schoener B (1962) Intracellular oxidation-reduction states in vivo. Science 137:499-508 de Valois JC, de Groot P (1975) Discrepancies in the results of flow measurements using different isotopes: 85Kr, 133Xe, and 14C-antipyrine. In: Cerebral Circulation and Metabolism (Langfitt TW, McHenry LC, Reivich M, Wollman H, eds), Berlin, Springer, pp 125-128 Eckman W W, Phair RD, Fenstermacher JD, Sokoloff L (1975) The influence of capillary permeability limitations on the measurement of regional cerebral blood flow. In: Cerebral Circulation and Metabolism (Langfitt TW, McHenry LC, Reivich M, Wollman H, eds), Berlin, Springer, pp 129-131 Eklof B, Lassen NA, Nilsson L, Norberg K, Siesjb BK (1973) Blood Flow and metabolic rate for oxygen in the cerebral cortex of the rat. Acta Physiol Scand88:587-589 Eklof B, Lassen NA, Nilsson L, Norberg K, Siesjb BK, Torlof P (1974) Regional cerebral blood flow in the rat measured by the tissue sampling technique: a critical evaluation using four indicators 14C-antipyrine, 14C-ethanol, 3H-water, and 133Xe. Acta Physiol Scand91:1-10 Fick A (1870) Uber die Messung des Blutquantums in den Herz ventrikeln. Verhandl d phys med Ges Zu Wurzburg 2:16 (quoted in its entirety by Hoff HE, Scott HF, New Engl J

Med239:122-148) Hanson EJ, Anderson RE, Sundt TM Jr (1975) Comparison of 85krypton and 133xenon cerebral blood flow measurements before, during, and following focal, incomplete ischemia in the squirrel monkey. Circ Res 36:18-26 Harper AM, Glass HI (1965) Effect of alterations in the arterial carbon dioxide tension on the blood flow through the cere bral cortex at normal and low arterial blood pressures. J

Neurol Neurosurg Psychiatry 28:449-452 Hl'\edt-Rasmussen K (1967) Regional cerebral blood flow; the intraarterial injection method. Acta Neural Scand (SuppI)27:

17-45 Hl'\edt-Rasmussen K, Sveinsdottir E, Lassen NA (1966) Re gional cerebral blood flow in man determined by intraar terial injection of radioactive inert gas. Circ Res 18:237-247 Ingvar DH, Lassen NA (1962) Regional blood flow of the cere bral cortex determined by krypton. Acta Physiol Scand

54:325-338 Kety SS (1949) Measurement of regional circulation by the local clearance of radioactive sodium. Am Heart J 38:321-328 Kety SS (1951) The theory and applications of the exchange of

inert gas at the lungs and tissues. Pharmacal Rev 3:1-41 Kety SS, Schmidt CF (1945) The determination of cerebral blood flow in man by the use of nitrous oxide in low concentra

tions. Am J Physiol 143:53-65 Lassen NA (1965) Blood flow of the cerebral cortex calculated from 85krypton-beta-clearance recorded over the exposed surface; evidence of inhomogeneity of flow. Acta Neural

Scand (Suppl) 14:24-28 Lassen NA, lngvar DH (1961) The blood flow of the cerebral cortex determined by radioactive krypton. Experientia (Basel) 17:42-43 Lassen NA, Munck 0 (1955) The cerebral blood flow in man determined by the use of radioactive krypton. Acta Physiol

Scand 33:30-49

Alexander SC, Wollman H, Cohen PJ, Chase PE, Behar B

Leniger-Follert E (1975) Interdependence of capillary flow and

(1964) Cerebrovascular response to Paco2 during halothane in man. J Appl Physiol 19:561-565

regional blood flow of the brain. In: Cerebral Circulation and Metabolism (Langfitt TW, McHenry LC, Reivich M,

Aim A, Bill A (1973) The effect of stimulation of the cervical sympathetic chain on retinal oxygen tension and on uveal,

Wollman H, eds), Berlin, Springer, pp 46-48 McHenry LC, Slocum HC, Bivens HE, Mayes HA, Hayes GJ (1965) Hyperventilation in awake and anesthetized man.

retinal, and cerebral blood flow in cats. Acta Physiol Scand

Arch Neural 12:270-277

88:84-94

J Cereb Blood Flow


FOCAL CORTICAL PERFUSION AND rCBF Neutze JM, Wlyer F, Rudolph AM (1968) Use of radioactive microspheres to assess distribution of cardiac output in rabbits. Am J Physiol 215:486-495 Ohta Y, Farhi LE (1979) Cerebral gas exchange: perfusion and diffusion limitations. J Appl Physiol Respir Environ Exercise

Physiol 46:1164-1168 Olesen J, Paulson OB, Lassen NA (1971) Regional cerebral blood flow in man determined by the initial slope of the clearance of intra-arterially injected 133Xe: theory of the method, normal values, error of measurement, correction for remaining radioactivity, relation to other flow param eters, and response to Paco2 changes. Stroke 2:519-540 Potchen EJ, Davis DO, Wharton T, Clifton J (1967) Effect of Compton scatter on regional cerebral blood flow determina tions with 133Xe (abstr). Clin Res 15:410-414 Reivich M (1964) Arterial PC02 and cerebral hemodynamics.

Am J Physiol 206:25-35

Reivich M (1969) Observation on exponential models of cerebral clearance curves. In: Research on the Cerebral Circulation (Meyer JS, Lechner H, Eichhorn 0, eds), Springfield, IL, Charles C Thomas, pp 135-144 Reivich M, Jehle J, Sokoloff L, Kety SS (1969a) Measurement of regional cerebral blood flow with antipyrine-14C in awake cats. J Appl Physiol 27:296-300 Reivich M, Slater R, Sano N (1969b) Further studies on experi-

213

mental models of cerebral clearance curves. In: Cerebral Blood Flow: Clinical and Experimental Results (Brock M, Fieschi C, Ingvar DH, Lasser NA, Schiirmann K, eds), Berlin, Springer-Verlag, pp 8-10 Sundt TM Jr, Anderson RE (1980a) Intracellular brain pH and the pathway of a fat soluble pH indicator across the blood brain barrier. Brain Res 186:355-364 Sundt TM Jr, Anderson RE (l980b) Umbelliferone as an intra cellular pH-sensitive fluorescent indicator and blood-brain barrier probe: instrumentation, calibration, and analysis. J

NeurophysioI44:60-75 Tomita M, Gotoh G (1981) Local cerebral blood flow values as estimated with diffusible tracers: validity of assumptions in normal and ischemic tissue. J Cereb Blood Flow Metab

1:403-411 Waltz AG, Wanek AR, Anderson RE (1972) Comparison of ana lytic methods for calculation of cerebral blood flow after in tracarotid injection of 133Xe. J Nucl Med13:66-72

Yamaguchi T, Regli F, Waltz AG (1971) Effect of PaC02 on hy peremia and ischemia in experimental cerebral infarction.

Stroke 2:139-147 Young W (1980) H2 clearance measurement of blood flow: a re view of technique and polarographic principles. Stroke

11:552-564

J Cereb Blood Flow
