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Measurement of regional blood flow by the 133Xenon inhalation method with an on-line computer
Compuf. Bid. Med.
Pergsmon
Press 1977. Vol. 7, pp. 143-157.
Printed in Great Britain.
MEASUREMENT OF REGIONAL BLOOD FLOW BY THE 133XENON INHALATION METHOD WITH AN ON-LINE COMPUTER* EDWIN M. WILSON, EDWARD L. WILLS, JARL RISBBRG,~ JAMBS H. HALSEY, JR., JAMES D.
GERARDand CHARMANE P. MAY
Stroke Acute Care Research Unit, Department of Neurology, University of Alabama Medical Center, Birmingham, AL 35294, U.S.A. (Receioed 8 January 1976; in revisedform 28 April 1976) A&me-A computer based multidetector system was developed for the measurement of regional cerebral blood flow (rCBF) by the 133Xenon inhalation technique. The computer portion of the system is characterized by on-line data acquisition, rapid data analysis and presentation of results. Special system features include programs which automatically determine end-tidal Xenon concentrations during the saturation and desaturation phases of the Bow measurement and which provide for automatic background subtraction, and a special pqmse counter-digital multiplexer-computer interface. The system provides convenience in handling acutely ill patients, ‘and assures reproducible positioning for serial measurements. Typical output format and partial results from 150 patient and normal subject measurements are presented. Cerebral blood how Xenon-133 Two-compartment analysis Data acquisition Displays On-line computer Isotope clearance Expired air sampling Biomedical computing
INTRODUCTION
The 133Xenon inhalation method for measurement of the regional cerebral blood flow (rCBF) was introdiced [l, 21 and later modified [3,4]. Compared to the intracarotid
technique[5,6], it offers advantages through the elimination of the carotid puncture, and the possibil$y of frequent measurements over prolonged periods. The. inhalation method also permits simultaneous bilateral measurements thus enabling an unmed hemisphere to serve as a reference for an a&&d one. Moreover, its safety permits measurements in normal volunteers to establish baseline flow values during resting conditions and during different functional tests. The principal .disadvantage of the method is the inclusion of extracerebral compartments which precludes an exact calculation of slow compartment flow rates (white matter blood flow) [4]. This paper describes a multidetector system for the measurement of rCBF by the Xenon inhalation technique using an on-line computer for data acquisition, rapid data an&&s and presentation of results, and convenient data storage. The system is primarily for studies in patients with cerebrovascular accidents, particularly stroke, but can be used for any other application of the technique as well. To date more than 1,000 studies have been made with this system on patients and normal volunteers. Only the preliminary results of some 150 studies are included here to illustrate the method. Additional clinical studies are published as separate reports [7]. METHODS General principles and theory of the technique The general principles and theory of the I33 Xenon inhalation technique will only be described briefly, since a detailed description recent$ has been published [S].
13’Xenon mixed with air is inhaled for a brief period (1 min). The time course of * Supported in part by NINDS Grants NS 08802 and NS 11109. t Dr. Risbesg was supported by grants from the Swedish Council for social Science Research and from the Swedish Medical Research Council. 143
EDWIN M. WILYON et al.
144
the concentration of the indicator in regions of the brain during and after the inhalation is determined by external collimated scintillation detectors. The rate of blood flow per unit mass of tissue “seen” by the detector is proportional to the rate of washout of the indicator. Based on the Fick principle the equation
Ci(t)
=fi
ewkit
C,(u) eki”du,
where Ci(t) = concentration of indicator in the ith tissue compartment at time t fi = blood flow per unit mass of the ith tissue compartment kl = fi/&, where di is the partition coefficient between the ith tissue compartment and blood C,(u) = concentration of indicator in arterial blood at time u = t, describes the relationship between flow rate and concentration. The convolution integral accounts for the recirculation of the indicator. As indicated in the equation the regions seen by the detectors are multi-compartmental with regard to flow rates. As originally suggested [3], the curves can be properly analysed by a 3 compartment model assuming that the three compartments correspond to grey matter, white matter, and extracerebral tissue, respectively. In the multi-compartment model the relationship between count rates and concentration is then given by N(t) = i
CC
&Ci(t),
i=l
N(t) = counts Wi = relative weight of compartment cc = proportionality constant. The three compartmental analysis has the disadvantage of requiring lengthy recordings (40 min). The present analysis is based on a simplified two compartment model allowing shorter recording times (11 min) (Obrist et al. [4,8]). The fast compartment is presumed to correspond to grey matter, while the slow compartment is assumed to be a combination of white matter and extracerebral tissues. The kl,fi, k2, and W, values are determined by solving the above equations (the uncertainty of Lz precludes an exact calculation of W,). The approximation to WI is based on an assumed A2 = 1.5 (see Veal1 and Mallet [9]). The “fractional flow” of the fast compartment (FF) is also calculated [8]. It indicates the fraction of the total absolute flow which represents rapidly perfused tissues. In addition an Initial Slope Index (ISI), reflecting mainly grey matter blood flow, is calculated from the slope of an early part of the curve corrected for recirculation [lo]. PHYSICAL
DESCRIPTION
Xenon transfer, storage and administration One curie of 133Xenon gas is commercially obtained in a 5 cc glass ampule. The ampule is crushed in a closed vessel and the gas is transferred by differential pressure into an initially evacuated 3-liter storage tank. Additional compressed air is flushed through the system and into the tank until an initial concentration of 50mCi/l is obtained in storage. The initial concentration must be known in order to calculate the concentration on any subsequent day due to the radioactive decay of 133Xenon (half-life: 5.2 days). Sufficient activity can then be transferred from storage via a flowmetered fill line to the breathing system for subsequent administration to the patient. Two options are available .for gas administration: an open-ended one-way from bag to patient to exhaust; and a rebreathing system. The rebreathing system, which is used
Measurement of regional cerebral blood flow
145
most often, is schematically shown in Fig. 1. The closed system consists of a breathing bag, a recirculation blower to insure adequate gas mixing, a CO2 absorber canister, and a one-way valve inside a lead-lined enclosure. This enclosure has a lead glass window which allows visual monitoring of the breathing bag during operation. The shielding is necessary to reduce exposure levels to personnel and to minimize the effects of scattered radiation. External to the enclosure are the tubing and valves (V, and V,) which allow the patient to be switched from the room air input-external exhaust operating mode to the closed mode for Xenon rebreathing. The exhaust tubing connected to V, terminates at the input of a 4800 cfm room exhaust fan. An additional fan is used to exhaust possible leakage from the storage tank cabinet and the rebreathing system enclosure. The mask-valve-tubing assembly is supported by a cantilevered rod which can be adjusted vertically and longitudinally. It can also be rotated about 90” from its operating position so as to be out of the way during head positioning. Xenon is administered to subjects at a nominal concentration of 5 mCi/l obtained by adding 40mCi of 133Xenon, 0.51 02, and air to load a total volume of 8 liters into the rebreathing system (4.5 liter dead space, 3.5 liter breathing bag). The O2 is included to compensate for that which is consumed during the one minute rebreathing period on the closed system. All calculations exclude the patient’s lung volume which, of course, dilutes the Xenon concentration to a value less than 5 mCi/l. The Xenon dosage administered by the above prescription is generally sufficient to obtain satisfactory peak counting rates (1000 cps) in the head curves for patients with CV disease, including the older group. Such count rates give acceptable statistical significance to the blood flow calculations [3]. The arterial concentration of 133Xenon is estimated by measurement of radioactivity in end-tidal air. A continuous sample of the expired air is drawn from the face mask by means of a pump and a thin “Teflon” catheter. The air sample passes through a shielded glass helix placed in front of a separate detector. Before evacuation to the outside the air sample is also analyzed for content of coz. Not shown in Fig. 1 are two valves and the tubing necessary to circulate the Xenon in the closed system through the air curve helix. This feature is especially useful in replenishing the Xenon concentration for serial CBF measurements. The counting rate in the air curve detector may be calibrated for a given Xenon concentration. Xenon may then be added for a subsequent measurement to bring the counting rate up to the preceding measurement value. The residual Xenon in the system, i.e. the Xenon
I I
I I
_
I I
I I I I I I I I I
Fig. 1. Rebre-athing system. Initially the breathing bag, blower and CO2 absorber operate as a single closed system in which a mixture of Xenon, O2 and air are circulated. The subject breathe-s room air via V, and exhales via V,. During Xenon administration the valves are switched so as to include the subject in the closed system. The mask is continuously sampled for Xenon and CO2 concentration.
146
EDWINM. WILSONet al.
not used in a preceding measurement, becomes a part of the activity used in a subseq.uent measurement. This conserves the Xenon used in the procedure and reduces the amount of radioactivity exhausted to the outside. Our experience with this system indicates a loss of 20-25 mCi per measurement with serial measurements whereas the open system would require 50-60 mCi for each measurement. Data collection system The data collection system consists of three major units: a detector table, a cabinet housing nuclear electronics and computer interface equipment, and a computer system. The detector table has an upper tray which supports the detector holder blocks, the air curve detector, the mask-valve-tubing assembly and the pickup head of the CO2 analyzer (see Fig. 2). This tray can be slid horizontally forward and backward so that the detectors can be properly and reproducibly positioned relative to the patient’s head. The detector holders are constructed of Plexiglas tubing arranged in a hexagonal pattern into which the detectors are placed. The detectors (Quartz-Silice) which have 3/4” x 3/4” NaI crystals are individually shielded and the entire assembly is also shielded. The detector blocks have eight detector locations on 1 7/8” centers with lead collimators 1” long by 3/4” ID. The detector blocks are located in “Plexiglas” guide strips so that they can be well separated initially to permit adjustment of head position and then moved adjacent to the head for the measurement. The guide strips also ensure that homologous pairs of detectors are always located coaxially. The upper fixed part of the table also supports the rebreathing system previously described. The lower portion of the table holds the high voltage system (consisting of power supplies, distribution panel and RC decouplers), the preamplifiers (Tennelec TC145) and the test pulse distribution panel. The cabinet contains the linear amplifier/single channel analyzer NIM modules (TC216). It also contains the nuclear electronics-computer interface bin which holds the counter, multiplexor and logic control modules. All permanent input/output cables exit from this cabinet in one rear bundle. Auxiliary front panel outputs permit the selection of channels for calibration with the multichannel pulse height analyzer (Nuclear Data ND2400) or for special counter monitoring or recording. An ancillary cabinet holds the multichannel pulse height analyzer system, the COZ analyzer console (Beckman LB-2), a two channel strip chart recorder (Texas Instrument PS-11-D), a test pulser (TC812), and an analog/digital counter. The computer system (depicted in Fig. 3) consists of a computer (Data General Nova 1230), a teletype terminal (ASR33) and a graphics display terminal (Tektronix 4010) to which a hard copy unit (Tektronix 4610) is attached. The computer contains a 28 K core memory, hardware floating point processor, a moving head disk with 1.2 million word storage, a high speed paper tape reader, a cassette unit, and a modem.
FUNCTIONAL
DESCRIPTION
Data acquisition. The signal flow for data acquisition is given in Fig. 4. Data acquisition consists of loading into the computer values corresponding to the counts per unit time for each of 14 cerebral regions and for the expired air sample. The pulse output from each detector is fed to a unity gain preamplifier whose output is then fed to a combination linear amplifier/single channel analyzer. A wide energy window is used (20-100 KeV) which includes both the gamma and X-ray peaks. Each single channel analyzer (SCA) output is fed to a 12 bit binary counter. The value in each counter is sequentially digitally multiplexed (parallel transfer) onto the computer bus at times selected by the computer. Data transfer from the computer interface is effected by two computer instructions, read and clear. The read instruction disables the counters for ca. 3OOnsec, transfers the contents of the addressed multiplexor-counter channel to the computer bus, resets and re-enables the counter, and increments the multiplexor address. The clear instruction
Fig. 2. Detector table. The sliding tray, shown in the partially forward position, holds two detector blocks which can be moved laterally with respect to the subjects head. Guide strips constrain the blocks so that pairs of detectors are always coaxial. Each block currently holds 7 collimated 1” detectors. The air curve detector is attached to the mask-tubing support assembly. The COZ analyzer head is adjacent. To the rear is the lead-lined breathing bag and CO2 absorber enclosure which also supports the circulating pump and valves. Below are the preamplifiers, high voltage power supplies and distribution panel.
149
Measurement of regional cerebral blood flow I2:Blf
LINEAR AMPtit?ER m
{
I
IPAl
AIR OETECTOR
7
COMPUTER
N
HEAD MTECTORS
: Uy
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PREAMPLIFIER IIS)
SINGLE CHANNEL ANALYSER (16)
H VP.S.
DIGITAL MULTIPL .EXER LOGIC CONTROL
I
CHANNEL TO MULTI-CHANNEL ANALYZER
SIGNAL FLOW BLOCK DIAGRAM
Fig. 3. Signal flow block diagram. Shows the relationship of the 16 channels of nuclear electronics and the computer interface consisting of 16 digital counters, a digital multiplexor and the interface control logic. 14 channels are used for separate regional detectors, one for the air curve detector and one for special purposes.
L_______l
L
I
1
YO NOVA 2110 XlTZ,
SYSTEM BLOCK DIAGRAM
Fig. 4. System block diagram. Shows the relationship of the nuclear electronics and computer interface to the major elements of the computer system for data acquisition, data analysis, data storage, display of results and program management. The analog to digital converter is to be added.
sets the multiplexor address to Channel 1 (air curve). Channel 1 is sampled at 0.2 set intervals and Channel 2-16 at 2.0 set intervals. Counter dead time for a 2 second period due to counter disable is ca. 7.5 psec or cu. 4 psec/sec‘ relative to a peak count rate of cu. 1,000 pulses/set. Data processing and display. Data processing and display are depicted in Fig. 5.* The data acquisition program called GETVAL has several functions. It uses the previously described counter interrogation in two phases: fist to determine background counts prior to inhalation and second to determine the time variation of ,counts during the measurement It establishes zero time as the time of crossing a threshold on the air curve. It determines the end-expiratory Xenon counts as the valleys during saturation phase (Xenon qq) and as peaks during the desaturation phase (Xenon off). It creates a file called CURVE’ consisting of head detectors and air sample detector data. This file is then loaded into disk under file identification NAM:00 where NAM are the * The software for rCBF measurements developed at this institution is available as FORTRAN listings.
EDWIN M. WILSONet al.
150
Fig. 5. System flow chart. Shows the normal sequence of programs (rectangles), temporary disk files generated (curved sides), and hard copy output (curved bottom).
first three letters of the patient’s last NAME and the following two digits represent the measurement number for the patient. The program called VIEW generates the display of raw data for each channel (see Fig. 6 for typical plot), and computes the time at which the air curve reaches 20% of its peak value. This time (usually cu. 1.7 min after time zero) is then used as the starting point for the analysis of all curves [S]. This start-fit time is indicated by the vertical line above the data point. The data analysis is done by a program called OBRST. It is essentially the program developed by Obrist [4] with only minor format modifications. It is based on the two compartment model previously described. Exponential clearance rates are calculated by a least squares fit to the observed data corrected for background. The clearance rates are related to flow rates by the partition coefficient for the tissue. The run time for this program is ca. 20-25 set per curve.
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J
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.**.a.*....... ..._.....
t
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9.
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LB.
s 11
Fig. 6. Typical plot from VIEW program showing raw data points. Beginning of start fit is indicated by vertical line. The ordinate values are in counts per six seconds.
Measurement of regional cerebral blood flow
151
Kl k”B LC
t:zz 9.712
ki LG LH RA PB RC Rn RE K
::z 8.896 0.649 8.631 8.688 8.681 8.686 8.589 8.623
rt
t:z
kB= 12.48 EP=l?B/ 95 ox: STRO-LP
DISABILITY SCORES 25-10-2%lW22-la-l&l@-10-10-18
Fig. 7. Typical tabulation of partialresults from the SUMMARY program. The designation LA indiitcs values from the detector in location A in the left hemisphere (see t.ext and Ref. 8 for description of parameters). Values for pCO,, Hgb, BP, diagnosis, and disability scores are entered in dialogue at the beginning of the SUMMARY program. The units of F1 (fI in text) are cc/gm/min.
Patient identifkation information and the results from OBRST are stored in three files-VALUES, COMET and PCURV for convenience in generating additional results for display in ditkrent format. VALUES and COMPT files are used in the program SUMMARY which generates the hard copy, a sample of which is shown in Fig. 7. SUMMARY is also used in dialogue to permit entry of arterial pCO,, Hemoglobin blood pressure, and diagnosis. Next, the program BIGBB generates the hard copy for the two hemisphere views with the values shown in the appropriate relative location. Figure 8 shows a typical plot for one hemisphere. The PCURV file is used in a program called PICX which generates a plot showing a superposition of raw data points on the curve generated by the computed values of K1, K2, etc. A typical plot is shown in Fig. 9. These permit visualization of the goodness of fit and were used extensively during the developmental phase when hard-
Fig. 8. Typical plot from the program BIGBB showing the values of primary interest in their respective regions.
EDWINM. WILSONet al.
152
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3.
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4.
6.
I,
1,
6.
~rr&tu
9.
9.
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Fig. 9. Typical plot from the program PICX showing the superposition on the raw data points.
I
12.
of the fitted curve
ware and software problems produced occasional spurious data points or results. The program is seldom used currently. Under a normal operating sequence the total elapsed time for positioning the patient, program keying, data acquisition, analysis and generation of hard copy for VIEW, SUMMARY, and BIGBB is cu. 25 min for 14 head curves. Since the patient raw data is saved in a permanent file, the sequence can be altered to permit successive data acquisition on different patients with analysis performed later. The disk data files are transferred to cassette for permanent tie. Additionally, these data files are transferred to the XDS Sigma 7 system for further statistical analysis. Measurement procedure
,The patient lies supine with his head near the end of the bed resting on a small pillow. The bed is then positioned next to the detector table and raised to the proper elevation. The detector table tray is then slid forward and adjusted for optimal hemispheric coverage. Land marks on the bridge of the nose and external auditory meatus relative to a rectangular Plexiglas grid are noted so that the same position of head relative to detectors can be obtained in subsequent studies. The mask holder is then rotated to midline position and the mask securely attached by rubber straps to insure no leaks. Initially the patient breathes room air until assurance of a satisfactory capnographic recording is obtained. The patient is then switched to the re-breathing system containing 133Xenon at 5 mCi/l for a period of one minute, and then returned to room air for a period of ten minutes. Immediately after the measurement, blood pressure is obtained by cuff and a 5 cc sample of arterial blood is drawn for pC02, Hgb, p02 and pH determinations. MATERIAL A total of 150 studies were made on 49 subjects. These subjects were divided into two groups: 1. Patients with cerebral infarction exhibiting hemiparesis, or hemiplegia, and subarachnoid hemorrhage. The age of this group ranged from 31 to 86 years with a mean age of 58 years. Forty studies were made on 19 patients in this group. 2. Apparently healthy volunteers ranging in age from 20 to 28 years (mean age of 23). 110 studies were made on 30 subjects in this group. RESULTS For the patient group the results shown in Table 1 were obtained. In the calculation of W, the blood-tissue partition coefficients were assumed to be 0.8 for the fast compart-
153
Measurement of regional cerebral blood flow
ment and 1.5 for the slow compartment [6,9]. The pC0, values for this group ranged from 24.0 to 42.4. After correcting for $0, for each patient (assuming a normal value of 40 with a 3% flow change per unit change of pC0,) [l l] the mean values were calculated to be: Table 1. Hemisphere mean values in the patient group (n = 40)
kz
fi m
SD
m
FF
WI m
SD
SD
m
ISI SD
m
SD
Left
50.4 f 9.57
0.084 f 0.015
33.7 + 5.1
0.675 + 0.052
32.86 f 5.90
Right
52.6 f 8.08
0.086 * 0.013
35.1 + 4.8
0.686 f 0.043
34.39 + 4.61
Left hemisphere fi = 56.5 + 8.31 Right hemisphere fi = 59.4 & 7.65 and (cc/100 gm/min). These means are based on 7 regional flow measurements for each hemisphere. A detailed analysis of these data including clinical correlates has been reported [7]. In the second more uniform group of young volunteers four measurements were performed on each subject. The results from two of these measurements made during resting conditions are reported here. The results from the other two measurements made during mental activation are presented elsewhere [7]. Considering 30 single studies a comparison of hemispheric means and standard deviations is shown in Table 2. The $0, was 40.8 + 2.1. Correcting individual flow values for pC0, (as before) and re-calculating the means gave values of fi = 71.6 f 7.6 in the left hemisphere and 71.7 + 7.6 in the right. The mean difference between Land R was 0.13 + 1.93 and the product moment correlation coefficient between Land R was 0.98. The difference infi between the normals and the patients was highly sign&ant (t-test, p < 0.001). The regional pattern within the hemispheres for the normal group is depicted in Fig. 10, where the mean flow values are given as percent of hemisphere mean and standard deviation. The product moment correlation coefficients for the different indices in 19 repeated studies, i.e. pairs .of studies made on 19 subjects under apparently identical conditions of rest with eyes closed made on different days, are given in Table 3. DISCUSSION As with any procedure utilizing radioactive materials, the radiation dosage to the patient is a prime consideration. The radiation dosage to patients has been calculated from the data of Loken and Kush [12]. For a CBF measurement with a one-minute rebreathing period and subsequent isotope washout, the radiation to the patient’s lungs (the primary organ) is approx. 140mrad with a Xenon concentration of 5 mCi/l in Table 2. Hemisphere mean values in the normal group (n = 30)
kz
fi m
SD
m
FF
WI SD
m
m
SD
ISI SD
m
SD
Left
73.7 f 8.8
0.105 + 0.023
42.2 f 3.8
0.776 f 0.022
51.8 + 7.0
Right
73.9 * 9.0
0.105 +_0.023
42.4 f 4.0
0.777 f 0.022
51.9 f 6.9
Table 3. Product moment correlations between 19 repeated studies f,
ka
W,
FF
IS1
Left
0.67
0.58
0.88
0.74
0.79
Right
0.67
0.59
0.88
0.73
0.80
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EDWINM. WILSONet al.
Fig. 10. Partial results from 20 separate studies on normal subjects. Values for each region normalized with respect to hemisphere mean are shown along with their standard deviation. The top number is the value for the left hemisphere region. The uniformity of values from opposite regions is evident despite the variation of tlow from frontal to occipital regions.
the rebreathing system. The whole body dose is approx. 200mrad. Thus there is no significant radiation hazard for the patient even for a relatively large number of serial measurements. The optimization of collimation geometry representing a trade-off between regional resolution, regional coverage (for a limited number of detectors) and counting statistics has not yet been effected. A parallel investigation of collimation based on phantom studies using a water-filled human skull is underway and will be reported separately. The adequacy of our current collimation is at least qualitatively apparent from the intra-hemispheric regional differences and conformity between opposite regions in the normal studies. A technetium brain scan is performed once on a large number of our patient population. Despite the relatively higher photopeak of technetium (143 KeV), the high dose and Compton scatter produces enough background within our energy discriminant window (20-100 KeV) to preclude rCBF studies for a period of 12-24 hr following a brain scan. One of the major advantages of the system, the rapid time for retrieval of results, is made possible by the interface of the nuclear electronics to a computer which is on-line for data acquisition and which has sufficient computing capability to rapidly solve the complex equations for multiple brain regions. This advantage is further enhanced by the disk operating system which permits rapid transfer of data files and has sufficient storage space to accommodate many patient data files. The display system (including generation of hard copy) has proven quite efficient. The display formats, of which typical copies have been shown, have proven useful for staff interpretation of change of patient flow states. The overall system flexibility facilitates additions to or alterations of display format. These features enable us to complete an entire study from initial positioning of the patient to generation of hard copy results in less than 25 min. Although the post-study washout of activity may proceed slowly in some patients, background levels are usually low enough to allow serial studies on an individual patient at hourly intervals because of the automatic background subtraction routine. If scheduling requires it, different patients can be studied at cu. 20 min intervals if the analysis and result display are
Measurement of regional cerebral blood flow
155
deferred. One of the reasons for the short time of procedure is the simplicity in properly and reproducibly positioning the patient with respect to the detectors. Another useful feature is the ease of transferring the required amount of 133Xenon into the rebreathing system before each study. Although two people at technician level or above are usually involved in making the measurement, it is possible for a single well-experienced person to conduct the entire operation including computer control. However, this adds several minutes to the total time. In the normal volunteers in which hemispheric mean flows were compared in 30 single studies a remarkable bilateral uniformity was observed in all flow and weight parameters. Since such uniformity would be expected on physiological grounds, these results show that the measurement technique and data analysis are bilaterally equivalent and supports the reliability of the method. This is further borne out by an examination of the regional pattern in opposite hemispheres. Although the regional mean f1 values, expressed as percent of hemispheric mean, varied from a minimum of 85.7 occipitally to a maximum of 112.2 frontally, the means in comparable regions differed by less than 1.0%. These regional variations offi fit well with results previously obtained with the intra-arterial technique [13,14]. The possibility of the bilateral uniformity being due to cross-talk was considered. It is known that some degree of cross-talk exists not only between opposite pairs of detectors but also between adjacent detectors. However, independent phantom studies (to be reported separately) have shown only a 2436% counting rate contribution due to radioactivity in the opposite hemisphere. Moreover, in measurements on other patients flow values differing by a factor as much as 2:l betwen homologous pairs and by 3 : 1 between adjacent channels have been observed. In contrast, the marked variability in mean flow in a given individual from day to day is evidenced by the much lower correlation coefficients in the 20 repeated studies (Table 3). This variability is probably due in part to marked differences in the mental and physical state of the subjects [7,10,15], factors which today are only partly understood. However, the most significant aspect of the normal bilateral uniformity and the large day to day variations is that in patients with stroke or other focal neurologic disorders the significance of unilateral regional flow changes as a function of time should be preferably determined relative to the unaffected or “reference” hemisphere. This suggests the need for simultaneous bilateral flow measurements when any degree of cerebrovascular pathology is suspect. The significant CBF differences between the young normals and the generally older stroke patients is partly due to the normal aging process. A more dominant factor is probably the cerebrovascular pathology which will be discussed in forthcoming publications. The interpretation of clinical data would also be simplified if “normal” subjects in successive age groups were studied to establish more comparable regional and hemispheric reference values. The system is being expanded to a total of 24 information channels. The additional data analysis and display time (some 3 to 4 min) will have negligible effect on the total procedural time. The addition of an analog multiplexor with an A/D converter will enable us to include other signals (e.g. EEG epochs, arterial pressure, heart rate, expiratory COz, etc.) in the on-line data acquisition. It is also expected that the scope of the rCBF studies will be enlarged to include patients with brain death, pre-and-postcardiac pacemaker implantation, head trauma, and pre-and-post-neurosurgery. The possibility of using “‘Xenon in lieu of ’ “3Xenon is also being considered because of several potential advantages. It is not a beta emitter, and therefore has a lower dosimetry (1.5 mR/mCi/min. for “‘Xenon vs 5.1 for ‘33Xenon). The two gamma photo peaks of 203 and 173 KeV are above technetium so that appropriate energy discrimination would permit rCBF measurements to be made relatively soon after brain scans (assuming detector and amplifier dead time is sufficiently low). Its longer half-life (36 vs 5.2 days) would reduce the amount of gas, especially in the rebreathing system. The additional C.R.M.
1/2---F
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EDWIN M. WILSONet al.
hemispheric cross-talk, i.e. counting from the contralateral hemisphere, because of the higher energy gamma should be relatively small (d* in muscle is 5 cm for “‘Xenon versus 3.9 cm for lJ3Xenon). The reduced efficiency of the crystals should be more than offset by the larger allowable concentrations. The potential advantages of ‘27Xenon are more than offset at present, however, due to its relative unavailability and high cost. SUMMARY This paper describes a computer based multidetector system which was developed for the measurement of regional cerebral blood flow (rCBF) by the 133Xenon inhalation technique. The computer portion of the system is characterized by on-line data acquisition, rapid data analysis and presentation of results (the total elapsed time from initial positioning of subject to generation of hard copy for 14 channels is less than 25 min). Special system features include programs which automatically determine end-tidal Xenon concentrations during the saturation and desaturation phases of the flow measurement and provide for automatic background subtraction. A special purpose counter digital multiplexor interface was developed which is controlled by two computer instructions. Data and results are output on a CRT terminal in alpha-numeric, graphical format with an attached hard copy unit, also used for program listings, etc. Typical output formats are included. The system also provi&s convenience in handling acutely ill patients to assure reproducible positioning for serial measurements and in administering the radioactive gas. Preliminary results are presented from 110 studies on 30 apparently healthy young volunteers and 40 studies on 19 patients with cerebra-vascular accidents. In the normal group single studies showed a significant regional variation in flow and weight parameters but a remarkable bilateral uniformity. In contrast, marked variability in mean flow for a given subject from day to day was observed, probably due to marked differences in the mental and physical state of the subjects. This bilateral uniformity and day to day variability suggests that in patients with stroke or other focal neurologic ‘disorders the significance of unilateral regional flow changes should be determined relative to the unaffected or “reference” hemisphere and supports the need for simultaneous bilateral measurements. The difference in blood flow of the fast compartment (fi) between the normals and the patients was highly significant (t-test, p < 0.001). Acknowledgement-The authors are indebted to Mr. L. N. LARKINfor engineering assistance during system development, and to Mr. A. V. WHITEfor technical assistance in the operation of the Cerebral Blood Flow Laboratory.
REFERENCES B. L. Mallett and N. Veall, Investigation of cerebral blood flow in hypertension using radioactive Xenon inhalation and extracranial recording. LMcet ii, 1081-1082 (1963). B. L. Mallett and N. VeaIl, The measurement of regional cerebral clearance rates in man using Xenon-133 inhalation and extracranial recording. Clin. Sci. 29, 179-191 (1%5). W. D. Obrist, H. K. Thompson, C. D. King and S. S. Wang, Determination of regional cerebral blood flow by inhalation of 133Xenon. Cir. Rex 3, 124-135 (1967). W. D. Obrist, H. K. Thompson, S. S. Wang and S. Cronquist, A simplified procedure for determining fast compartment rCBF by ‘33Xenon inhalation. In. Brain and Blood Flow (Ed. R. W. Ross-Russel). Pitman, London. 11-15 (1971). 5. N. A. Lassen, K. Hsedt-Rasmussen, S. C. Sorensen, E. Skinhej, S. Cronquist, B. Bodforss and D. H. Ingvar, Regional cerebral blood flow in man determined by Krypton *5. Neurology 13, 719-727 (1963). 6. K. Heedt-Rasmussen, E. Sveinsdottir and N. A. Lassen, Regional cerebral blood flow in man determined by intra-aerterial injection of radioactive inert gas. Circulation Res. 18, 237-247 (1966). I. J. Risberg, J. H. Halsey, E. L. Wills and E. M. Wilson, Hemispheric specialization in normal man studied by bilateral measurements of the regional cerebral blood flow. Brain 98, 511-524 (1975). 8. W. D. Obrist, H. K. Thompson, H. S. Wang and W. E. Wilkenson, Regional cerebral blood flow estimated by ‘33Xenon inhalation. Stroke 6, 245-256 (1975). 9. N. Veal1 and B. L. Mallett, The partition of trace amounts of Xenon between human blood and brain tissues at 37°C. Phys. Med. Biol. IO, 375-380 (1965). 10. J. Risberg, Z. Ali, E. M. Wilson, E. L. Wills and J. H. Halsey, Regional cerebral blood flow by ‘33Xenon inhalation. Stroke 6, 142-148 (1975).
Measurement of regional cerebral blood flow 11. S. C. Alexander, H. Wollman, P. J. Cohen, P. E. Chase and M. Behar, Cerebrovascular
12.
13.
14.
15.
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response to PaCOl during halothane anesthesia in man. J. appl. Physiol. 19, 561-565 (1964). M. K. Loken and G. S. Kush, Handling, uses, and radiation dosimetry of Xenon-133. In Med. Radionuclides: Radiation Dose and Eficts. (Eds. R. J. Cloutier, C. L. Edwards and W. S. Snyder) AEC Div. Tech. Info. Oak Ridge, Tn, pp. 253-270 (1970). I. M. S. Wilkinson, J. W. D. Bull, G. H. Duboulay, J. Marshall, R. W. Ross-Russell and L. Symon, Regional blood flow in the normal cerebral hemisphere. J. Neural. Neurosurg. Psych&. 32, 367-378 (1969). E. Sveinsdottir, P. Thorlof, J. Risberg, D. H. Ingvar and N. A. Lassen, Calculation of regional cerebral blood flow (rCBF): Initial-slope-index compared to height-over-total-area values. In Brain and Blood Flow: Proc. 4th Int. Symp. on the Regulation of Cerebral Blood Flow. London, p. 85 (1970). J. Risberg and D. H. Ingvar, Patterns of activation in the grey matter of the dominant hemisphere during memorization and reasoning. A study of regional cerebral blood flow changes during psychological testing in a group of neurologically normal patients. Brain %, 737-756 (1973). About the AII~~-ED~IN
M. WILSONreceived his B.S. degree in Electrical Engineering and in Business and Engineering Administration from the Massachussetts Institute of Technology and an Sc.D. in Biomedical Engineering from the University of Virginia in 1967. He has had industrial experience in the area of feedback control systems. His work at the U.A.B. has involved biomedical engineering applications in cardiology, particularly in blood flow measurements. More recently Dr. Wilson has been engaged in research in neurology with emphasis on monitoring patients with cerebrovascular accidents and experimental animal models of cerebral ischemia and infarction using mini-computers and special purpose electronic systems. He teaches courses in digital and analog computers and in medical instrumentation. Dr. Wilson is currently Associate Professor in the School of Engineering and holds joint appointments in the Department of Information Science and the Department of Neurology. About the Author-EDWARD L. WILLS received the B.S. and M.S. degrees from Auburn Univer-
sity and the Ph.D. in physics from the University of Virginia in 1968 with research at the Space Radiation Effects Laboratory synchrocyclotron. As a Research Associate and Assistant Professor at the University of Georgia he was engaged in the development of the UGA 5MV Van de Graalf facility and research in isobaric analog states. Dr. Wills joined the U.A.B. in 1973 where he is currently Assistant Professor in the Department of Physics and is involved with radioisotope techniques with the Department of Neurology. Dr. Wills is a member of the American Physical Society, Phi Kappa Phi, and Sigma Xi. A. RISEJIGreceived a Ph.D. in Psychology from the University of Lund, Sweden, in 1969, where for 10 years he has been interested in cerebral blood flow as an index of mental activity. He was Research Associate in the Department of Neurology at the University of Alabama Medical Center in Birmingham, Alabama 1973-1974. Dr. Risberg is Associate Professor of Psychology at the University Hospital, Lund, Sweden where he is director of the laboratory of neuropsychology.
About the Author-JmL
About the Author-JAr+ms H. HALSEY, JR., M.D. is a 1959 graduate of Yale University Medical School and had his specialty training in Neurology at the University of North Carolina. He is principally interested in development and application of new monitoring methods for clinical management of patients with stroke. Dr. Halsey is Professor and Chairman, Department of Neurology at the University of Alabama Medical Center in Birmingham, Alabama where is has been a faculty member since 1965. About the Author-J_aas
D. GERARDreceived his B.S. degree in mathematics from Birmingham Southern College in 1970. He is currently employed r&Systems Analyst in the Division of Biophysical Sciences, U.A.B. Medical Center engaged primarily in computer processing of exercise ECG data and continuous arrhythmia analysis. He is a member of the Association for Computer Machinery. P. MAY received her B.S. degree in mathematics from Spring Hill College in 1972 and her M.C.S. degree from Texas A & M University in 1973. During 1974, she held a joint appointment of instructor in the Department of Information Sciences and the Department of Neurology at the University of Alabama in Birmingham. Since October, 1974, she has been a part-time instructor and has been pursuing a Ph.D. degree in Information Sciences. She is currently developing her thesis topic in the area of data base equivalence. About the Author-Chmmm
Pergsmon
Press 1977. Vol. 7, pp. 143-157.
Printed in Great Britain.
MEASUREMENT OF REGIONAL BLOOD FLOW BY THE 133XENON INHALATION METHOD WITH AN ON-LINE COMPUTER* EDWIN M. WILSON, EDWARD L. WILLS, JARL RISBBRG,~ JAMBS H. HALSEY, JR., JAMES D.
GERARDand CHARMANE P. MAY
Stroke Acute Care Research Unit, Department of Neurology, University of Alabama Medical Center, Birmingham, AL 35294, U.S.A. (Receioed 8 January 1976; in revisedform 28 April 1976) A&me-A computer based multidetector system was developed for the measurement of regional cerebral blood flow (rCBF) by the 133Xenon inhalation technique. The computer portion of the system is characterized by on-line data acquisition, rapid data analysis and presentation of results. Special system features include programs which automatically determine end-tidal Xenon concentrations during the saturation and desaturation phases of the Bow measurement and which provide for automatic background subtraction, and a special pqmse counter-digital multiplexer-computer interface. The system provides convenience in handling acutely ill patients, ‘and assures reproducible positioning for serial measurements. Typical output format and partial results from 150 patient and normal subject measurements are presented. Cerebral blood how Xenon-133 Two-compartment analysis Data acquisition Displays On-line computer Isotope clearance Expired air sampling Biomedical computing
INTRODUCTION
The 133Xenon inhalation method for measurement of the regional cerebral blood flow (rCBF) was introdiced [l, 21 and later modified [3,4]. Compared to the intracarotid
technique[5,6], it offers advantages through the elimination of the carotid puncture, and the possibil$y of frequent measurements over prolonged periods. The. inhalation method also permits simultaneous bilateral measurements thus enabling an unmed hemisphere to serve as a reference for an a&&d one. Moreover, its safety permits measurements in normal volunteers to establish baseline flow values during resting conditions and during different functional tests. The principal .disadvantage of the method is the inclusion of extracerebral compartments which precludes an exact calculation of slow compartment flow rates (white matter blood flow) [4]. This paper describes a multidetector system for the measurement of rCBF by the Xenon inhalation technique using an on-line computer for data acquisition, rapid data an&&s and presentation of results, and convenient data storage. The system is primarily for studies in patients with cerebrovascular accidents, particularly stroke, but can be used for any other application of the technique as well. To date more than 1,000 studies have been made with this system on patients and normal volunteers. Only the preliminary results of some 150 studies are included here to illustrate the method. Additional clinical studies are published as separate reports [7]. METHODS General principles and theory of the technique The general principles and theory of the I33 Xenon inhalation technique will only be described briefly, since a detailed description recent$ has been published [S].
13’Xenon mixed with air is inhaled for a brief period (1 min). The time course of * Supported in part by NINDS Grants NS 08802 and NS 11109. t Dr. Risbesg was supported by grants from the Swedish Council for social Science Research and from the Swedish Medical Research Council. 143
EDWIN M. WILYON et al.
144
the concentration of the indicator in regions of the brain during and after the inhalation is determined by external collimated scintillation detectors. The rate of blood flow per unit mass of tissue “seen” by the detector is proportional to the rate of washout of the indicator. Based on the Fick principle the equation
Ci(t)
=fi
ewkit
C,(u) eki”du,
where Ci(t) = concentration of indicator in the ith tissue compartment at time t fi = blood flow per unit mass of the ith tissue compartment kl = fi/&, where di is the partition coefficient between the ith tissue compartment and blood C,(u) = concentration of indicator in arterial blood at time u = t, describes the relationship between flow rate and concentration. The convolution integral accounts for the recirculation of the indicator. As indicated in the equation the regions seen by the detectors are multi-compartmental with regard to flow rates. As originally suggested [3], the curves can be properly analysed by a 3 compartment model assuming that the three compartments correspond to grey matter, white matter, and extracerebral tissue, respectively. In the multi-compartment model the relationship between count rates and concentration is then given by N(t) = i
CC
&Ci(t),
i=l
N(t) = counts Wi = relative weight of compartment cc = proportionality constant. The three compartmental analysis has the disadvantage of requiring lengthy recordings (40 min). The present analysis is based on a simplified two compartment model allowing shorter recording times (11 min) (Obrist et al. [4,8]). The fast compartment is presumed to correspond to grey matter, while the slow compartment is assumed to be a combination of white matter and extracerebral tissues. The kl,fi, k2, and W, values are determined by solving the above equations (the uncertainty of Lz precludes an exact calculation of W,). The approximation to WI is based on an assumed A2 = 1.5 (see Veal1 and Mallet [9]). The “fractional flow” of the fast compartment (FF) is also calculated [8]. It indicates the fraction of the total absolute flow which represents rapidly perfused tissues. In addition an Initial Slope Index (ISI), reflecting mainly grey matter blood flow, is calculated from the slope of an early part of the curve corrected for recirculation [lo]. PHYSICAL
DESCRIPTION
Xenon transfer, storage and administration One curie of 133Xenon gas is commercially obtained in a 5 cc glass ampule. The ampule is crushed in a closed vessel and the gas is transferred by differential pressure into an initially evacuated 3-liter storage tank. Additional compressed air is flushed through the system and into the tank until an initial concentration of 50mCi/l is obtained in storage. The initial concentration must be known in order to calculate the concentration on any subsequent day due to the radioactive decay of 133Xenon (half-life: 5.2 days). Sufficient activity can then be transferred from storage via a flowmetered fill line to the breathing system for subsequent administration to the patient. Two options are available .for gas administration: an open-ended one-way from bag to patient to exhaust; and a rebreathing system. The rebreathing system, which is used
Measurement of regional cerebral blood flow
145
most often, is schematically shown in Fig. 1. The closed system consists of a breathing bag, a recirculation blower to insure adequate gas mixing, a CO2 absorber canister, and a one-way valve inside a lead-lined enclosure. This enclosure has a lead glass window which allows visual monitoring of the breathing bag during operation. The shielding is necessary to reduce exposure levels to personnel and to minimize the effects of scattered radiation. External to the enclosure are the tubing and valves (V, and V,) which allow the patient to be switched from the room air input-external exhaust operating mode to the closed mode for Xenon rebreathing. The exhaust tubing connected to V, terminates at the input of a 4800 cfm room exhaust fan. An additional fan is used to exhaust possible leakage from the storage tank cabinet and the rebreathing system enclosure. The mask-valve-tubing assembly is supported by a cantilevered rod which can be adjusted vertically and longitudinally. It can also be rotated about 90” from its operating position so as to be out of the way during head positioning. Xenon is administered to subjects at a nominal concentration of 5 mCi/l obtained by adding 40mCi of 133Xenon, 0.51 02, and air to load a total volume of 8 liters into the rebreathing system (4.5 liter dead space, 3.5 liter breathing bag). The O2 is included to compensate for that which is consumed during the one minute rebreathing period on the closed system. All calculations exclude the patient’s lung volume which, of course, dilutes the Xenon concentration to a value less than 5 mCi/l. The Xenon dosage administered by the above prescription is generally sufficient to obtain satisfactory peak counting rates (1000 cps) in the head curves for patients with CV disease, including the older group. Such count rates give acceptable statistical significance to the blood flow calculations [3]. The arterial concentration of 133Xenon is estimated by measurement of radioactivity in end-tidal air. A continuous sample of the expired air is drawn from the face mask by means of a pump and a thin “Teflon” catheter. The air sample passes through a shielded glass helix placed in front of a separate detector. Before evacuation to the outside the air sample is also analyzed for content of coz. Not shown in Fig. 1 are two valves and the tubing necessary to circulate the Xenon in the closed system through the air curve helix. This feature is especially useful in replenishing the Xenon concentration for serial CBF measurements. The counting rate in the air curve detector may be calibrated for a given Xenon concentration. Xenon may then be added for a subsequent measurement to bring the counting rate up to the preceding measurement value. The residual Xenon in the system, i.e. the Xenon
I I
I I
_
I I
I I I I I I I I I
Fig. 1. Rebre-athing system. Initially the breathing bag, blower and CO2 absorber operate as a single closed system in which a mixture of Xenon, O2 and air are circulated. The subject breathe-s room air via V, and exhales via V,. During Xenon administration the valves are switched so as to include the subject in the closed system. The mask is continuously sampled for Xenon and CO2 concentration.
146
EDWINM. WILSONet al.
not used in a preceding measurement, becomes a part of the activity used in a subseq.uent measurement. This conserves the Xenon used in the procedure and reduces the amount of radioactivity exhausted to the outside. Our experience with this system indicates a loss of 20-25 mCi per measurement with serial measurements whereas the open system would require 50-60 mCi for each measurement. Data collection system The data collection system consists of three major units: a detector table, a cabinet housing nuclear electronics and computer interface equipment, and a computer system. The detector table has an upper tray which supports the detector holder blocks, the air curve detector, the mask-valve-tubing assembly and the pickup head of the CO2 analyzer (see Fig. 2). This tray can be slid horizontally forward and backward so that the detectors can be properly and reproducibly positioned relative to the patient’s head. The detector holders are constructed of Plexiglas tubing arranged in a hexagonal pattern into which the detectors are placed. The detectors (Quartz-Silice) which have 3/4” x 3/4” NaI crystals are individually shielded and the entire assembly is also shielded. The detector blocks have eight detector locations on 1 7/8” centers with lead collimators 1” long by 3/4” ID. The detector blocks are located in “Plexiglas” guide strips so that they can be well separated initially to permit adjustment of head position and then moved adjacent to the head for the measurement. The guide strips also ensure that homologous pairs of detectors are always located coaxially. The upper fixed part of the table also supports the rebreathing system previously described. The lower portion of the table holds the high voltage system (consisting of power supplies, distribution panel and RC decouplers), the preamplifiers (Tennelec TC145) and the test pulse distribution panel. The cabinet contains the linear amplifier/single channel analyzer NIM modules (TC216). It also contains the nuclear electronics-computer interface bin which holds the counter, multiplexor and logic control modules. All permanent input/output cables exit from this cabinet in one rear bundle. Auxiliary front panel outputs permit the selection of channels for calibration with the multichannel pulse height analyzer (Nuclear Data ND2400) or for special counter monitoring or recording. An ancillary cabinet holds the multichannel pulse height analyzer system, the COZ analyzer console (Beckman LB-2), a two channel strip chart recorder (Texas Instrument PS-11-D), a test pulser (TC812), and an analog/digital counter. The computer system (depicted in Fig. 3) consists of a computer (Data General Nova 1230), a teletype terminal (ASR33) and a graphics display terminal (Tektronix 4010) to which a hard copy unit (Tektronix 4610) is attached. The computer contains a 28 K core memory, hardware floating point processor, a moving head disk with 1.2 million word storage, a high speed paper tape reader, a cassette unit, and a modem.
FUNCTIONAL
DESCRIPTION
Data acquisition. The signal flow for data acquisition is given in Fig. 4. Data acquisition consists of loading into the computer values corresponding to the counts per unit time for each of 14 cerebral regions and for the expired air sample. The pulse output from each detector is fed to a unity gain preamplifier whose output is then fed to a combination linear amplifier/single channel analyzer. A wide energy window is used (20-100 KeV) which includes both the gamma and X-ray peaks. Each single channel analyzer (SCA) output is fed to a 12 bit binary counter. The value in each counter is sequentially digitally multiplexed (parallel transfer) onto the computer bus at times selected by the computer. Data transfer from the computer interface is effected by two computer instructions, read and clear. The read instruction disables the counters for ca. 3OOnsec, transfers the contents of the addressed multiplexor-counter channel to the computer bus, resets and re-enables the counter, and increments the multiplexor address. The clear instruction
Fig. 2. Detector table. The sliding tray, shown in the partially forward position, holds two detector blocks which can be moved laterally with respect to the subjects head. Guide strips constrain the blocks so that pairs of detectors are always coaxial. Each block currently holds 7 collimated 1” detectors. The air curve detector is attached to the mask-tubing support assembly. The COZ analyzer head is adjacent. To the rear is the lead-lined breathing bag and CO2 absorber enclosure which also supports the circulating pump and valves. Below are the preamplifiers, high voltage power supplies and distribution panel.
149
Measurement of regional cerebral blood flow I2:Blf
LINEAR AMPtit?ER m
{
I
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AIR OETECTOR
7
COMPUTER
N
HEAD MTECTORS
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I
PREAMPLIFIER IIS)
SINGLE CHANNEL ANALYSER (16)
H VP.S.
DIGITAL MULTIPL .EXER LOGIC CONTROL
I
CHANNEL TO MULTI-CHANNEL ANALYZER
SIGNAL FLOW BLOCK DIAGRAM
Fig. 3. Signal flow block diagram. Shows the relationship of the 16 channels of nuclear electronics and the computer interface consisting of 16 digital counters, a digital multiplexor and the interface control logic. 14 channels are used for separate regional detectors, one for the air curve detector and one for special purposes.
L_______l
L
I
1
YO NOVA 2110 XlTZ,
SYSTEM BLOCK DIAGRAM
Fig. 4. System block diagram. Shows the relationship of the nuclear electronics and computer interface to the major elements of the computer system for data acquisition, data analysis, data storage, display of results and program management. The analog to digital converter is to be added.
sets the multiplexor address to Channel 1 (air curve). Channel 1 is sampled at 0.2 set intervals and Channel 2-16 at 2.0 set intervals. Counter dead time for a 2 second period due to counter disable is ca. 7.5 psec or cu. 4 psec/sec‘ relative to a peak count rate of cu. 1,000 pulses/set. Data processing and display. Data processing and display are depicted in Fig. 5.* The data acquisition program called GETVAL has several functions. It uses the previously described counter interrogation in two phases: fist to determine background counts prior to inhalation and second to determine the time variation of ,counts during the measurement It establishes zero time as the time of crossing a threshold on the air curve. It determines the end-expiratory Xenon counts as the valleys during saturation phase (Xenon qq) and as peaks during the desaturation phase (Xenon off). It creates a file called CURVE’ consisting of head detectors and air sample detector data. This file is then loaded into disk under file identification NAM:00 where NAM are the * The software for rCBF measurements developed at this institution is available as FORTRAN listings.
EDWIN M. WILSONet al.
150
Fig. 5. System flow chart. Shows the normal sequence of programs (rectangles), temporary disk files generated (curved sides), and hard copy output (curved bottom).
first three letters of the patient’s last NAME and the following two digits represent the measurement number for the patient. The program called VIEW generates the display of raw data for each channel (see Fig. 6 for typical plot), and computes the time at which the air curve reaches 20% of its peak value. This time (usually cu. 1.7 min after time zero) is then used as the starting point for the analysis of all curves [S]. This start-fit time is indicated by the vertical line above the data point. The data analysis is done by a program called OBRST. It is essentially the program developed by Obrist [4] with only minor format modifications. It is based on the two compartment model previously described. Exponential clearance rates are calculated by a least squares fit to the observed data corrected for background. The clearance rates are related to flow rates by the partition coefficient for the tissue. The run time for this program is ca. 20-25 set per curve.
.. .... ‘..
.
J
3m@_
‘.. ‘.. ..‘..,, “....,,,_ ‘.‘....................
2@m_ lwe_
. I
1 i
t ;:
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4
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I T1t&N>
.**.a.*....... ..._.....
t
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7.
8.
9.
r
LB.
s 11
Fig. 6. Typical plot from VIEW program showing raw data points. Beginning of start fit is indicated by vertical line. The ordinate values are in counts per six seconds.
Measurement of regional cerebral blood flow
151
Kl k”B LC
t:zz 9.712
ki LG LH RA PB RC Rn RE K
::z 8.896 0.649 8.631 8.688 8.681 8.686 8.589 8.623
rt
t:z
kB= 12.48 EP=l?B/ 95 ox: STRO-LP
DISABILITY SCORES 25-10-2%lW22-la-l&l@-10-10-18
Fig. 7. Typical tabulation of partialresults from the SUMMARY program. The designation LA indiitcs values from the detector in location A in the left hemisphere (see t.ext and Ref. 8 for description of parameters). Values for pCO,, Hgb, BP, diagnosis, and disability scores are entered in dialogue at the beginning of the SUMMARY program. The units of F1 (fI in text) are cc/gm/min.
Patient identifkation information and the results from OBRST are stored in three files-VALUES, COMET and PCURV for convenience in generating additional results for display in ditkrent format. VALUES and COMPT files are used in the program SUMMARY which generates the hard copy, a sample of which is shown in Fig. 7. SUMMARY is also used in dialogue to permit entry of arterial pCO,, Hemoglobin blood pressure, and diagnosis. Next, the program BIGBB generates the hard copy for the two hemisphere views with the values shown in the appropriate relative location. Figure 8 shows a typical plot for one hemisphere. The PCURV file is used in a program called PICX which generates a plot showing a superposition of raw data points on the curve generated by the computed values of K1, K2, etc. A typical plot is shown in Fig. 9. These permit visualization of the goodness of fit and were used extensively during the developmental phase when hard-
Fig. 8. Typical plot from the program BIGBB showing the values of primary interest in their respective regions.
EDWINM. WILSONet al.
152
I,
2.
3.
I
I,
4.
6.
I,
1,
6.
~rr&tu
9.
9.
I
le.
II.
Fig. 9. Typical plot from the program PICX showing the superposition on the raw data points.
I
12.
of the fitted curve
ware and software problems produced occasional spurious data points or results. The program is seldom used currently. Under a normal operating sequence the total elapsed time for positioning the patient, program keying, data acquisition, analysis and generation of hard copy for VIEW, SUMMARY, and BIGBB is cu. 25 min for 14 head curves. Since the patient raw data is saved in a permanent file, the sequence can be altered to permit successive data acquisition on different patients with analysis performed later. The disk data files are transferred to cassette for permanent tie. Additionally, these data files are transferred to the XDS Sigma 7 system for further statistical analysis. Measurement procedure
,The patient lies supine with his head near the end of the bed resting on a small pillow. The bed is then positioned next to the detector table and raised to the proper elevation. The detector table tray is then slid forward and adjusted for optimal hemispheric coverage. Land marks on the bridge of the nose and external auditory meatus relative to a rectangular Plexiglas grid are noted so that the same position of head relative to detectors can be obtained in subsequent studies. The mask holder is then rotated to midline position and the mask securely attached by rubber straps to insure no leaks. Initially the patient breathes room air until assurance of a satisfactory capnographic recording is obtained. The patient is then switched to the re-breathing system containing 133Xenon at 5 mCi/l for a period of one minute, and then returned to room air for a period of ten minutes. Immediately after the measurement, blood pressure is obtained by cuff and a 5 cc sample of arterial blood is drawn for pC02, Hgb, p02 and pH determinations. MATERIAL A total of 150 studies were made on 49 subjects. These subjects were divided into two groups: 1. Patients with cerebral infarction exhibiting hemiparesis, or hemiplegia, and subarachnoid hemorrhage. The age of this group ranged from 31 to 86 years with a mean age of 58 years. Forty studies were made on 19 patients in this group. 2. Apparently healthy volunteers ranging in age from 20 to 28 years (mean age of 23). 110 studies were made on 30 subjects in this group. RESULTS For the patient group the results shown in Table 1 were obtained. In the calculation of W, the blood-tissue partition coefficients were assumed to be 0.8 for the fast compart-
153
Measurement of regional cerebral blood flow
ment and 1.5 for the slow compartment [6,9]. The pC0, values for this group ranged from 24.0 to 42.4. After correcting for $0, for each patient (assuming a normal value of 40 with a 3% flow change per unit change of pC0,) [l l] the mean values were calculated to be: Table 1. Hemisphere mean values in the patient group (n = 40)
kz
fi m
SD
m
FF
WI m
SD
SD
m
ISI SD
m
SD
Left
50.4 f 9.57
0.084 f 0.015
33.7 + 5.1
0.675 + 0.052
32.86 f 5.90
Right
52.6 f 8.08
0.086 * 0.013
35.1 + 4.8
0.686 f 0.043
34.39 + 4.61
Left hemisphere fi = 56.5 + 8.31 Right hemisphere fi = 59.4 & 7.65 and (cc/100 gm/min). These means are based on 7 regional flow measurements for each hemisphere. A detailed analysis of these data including clinical correlates has been reported [7]. In the second more uniform group of young volunteers four measurements were performed on each subject. The results from two of these measurements made during resting conditions are reported here. The results from the other two measurements made during mental activation are presented elsewhere [7]. Considering 30 single studies a comparison of hemispheric means and standard deviations is shown in Table 2. The $0, was 40.8 + 2.1. Correcting individual flow values for pC0, (as before) and re-calculating the means gave values of fi = 71.6 f 7.6 in the left hemisphere and 71.7 + 7.6 in the right. The mean difference between Land R was 0.13 + 1.93 and the product moment correlation coefficient between Land R was 0.98. The difference infi between the normals and the patients was highly sign&ant (t-test, p < 0.001). The regional pattern within the hemispheres for the normal group is depicted in Fig. 10, where the mean flow values are given as percent of hemisphere mean and standard deviation. The product moment correlation coefficients for the different indices in 19 repeated studies, i.e. pairs .of studies made on 19 subjects under apparently identical conditions of rest with eyes closed made on different days, are given in Table 3. DISCUSSION As with any procedure utilizing radioactive materials, the radiation dosage to the patient is a prime consideration. The radiation dosage to patients has been calculated from the data of Loken and Kush [12]. For a CBF measurement with a one-minute rebreathing period and subsequent isotope washout, the radiation to the patient’s lungs (the primary organ) is approx. 140mrad with a Xenon concentration of 5 mCi/l in Table 2. Hemisphere mean values in the normal group (n = 30)
kz
fi m
SD
m
FF
WI SD
m
m
SD
ISI SD
m
SD
Left
73.7 f 8.8
0.105 + 0.023
42.2 f 3.8
0.776 f 0.022
51.8 + 7.0
Right
73.9 * 9.0
0.105 +_0.023
42.4 f 4.0
0.777 f 0.022
51.9 f 6.9
Table 3. Product moment correlations between 19 repeated studies f,
ka
W,
FF
IS1
Left
0.67
0.58
0.88
0.74
0.79
Right
0.67
0.59
0.88
0.73
0.80
154
EDWINM. WILSONet al.
Fig. 10. Partial results from 20 separate studies on normal subjects. Values for each region normalized with respect to hemisphere mean are shown along with their standard deviation. The top number is the value for the left hemisphere region. The uniformity of values from opposite regions is evident despite the variation of tlow from frontal to occipital regions.
the rebreathing system. The whole body dose is approx. 200mrad. Thus there is no significant radiation hazard for the patient even for a relatively large number of serial measurements. The optimization of collimation geometry representing a trade-off between regional resolution, regional coverage (for a limited number of detectors) and counting statistics has not yet been effected. A parallel investigation of collimation based on phantom studies using a water-filled human skull is underway and will be reported separately. The adequacy of our current collimation is at least qualitatively apparent from the intra-hemispheric regional differences and conformity between opposite regions in the normal studies. A technetium brain scan is performed once on a large number of our patient population. Despite the relatively higher photopeak of technetium (143 KeV), the high dose and Compton scatter produces enough background within our energy discriminant window (20-100 KeV) to preclude rCBF studies for a period of 12-24 hr following a brain scan. One of the major advantages of the system, the rapid time for retrieval of results, is made possible by the interface of the nuclear electronics to a computer which is on-line for data acquisition and which has sufficient computing capability to rapidly solve the complex equations for multiple brain regions. This advantage is further enhanced by the disk operating system which permits rapid transfer of data files and has sufficient storage space to accommodate many patient data files. The display system (including generation of hard copy) has proven quite efficient. The display formats, of which typical copies have been shown, have proven useful for staff interpretation of change of patient flow states. The overall system flexibility facilitates additions to or alterations of display format. These features enable us to complete an entire study from initial positioning of the patient to generation of hard copy results in less than 25 min. Although the post-study washout of activity may proceed slowly in some patients, background levels are usually low enough to allow serial studies on an individual patient at hourly intervals because of the automatic background subtraction routine. If scheduling requires it, different patients can be studied at cu. 20 min intervals if the analysis and result display are
Measurement of regional cerebral blood flow
155
deferred. One of the reasons for the short time of procedure is the simplicity in properly and reproducibly positioning the patient with respect to the detectors. Another useful feature is the ease of transferring the required amount of 133Xenon into the rebreathing system before each study. Although two people at technician level or above are usually involved in making the measurement, it is possible for a single well-experienced person to conduct the entire operation including computer control. However, this adds several minutes to the total time. In the normal volunteers in which hemispheric mean flows were compared in 30 single studies a remarkable bilateral uniformity was observed in all flow and weight parameters. Since such uniformity would be expected on physiological grounds, these results show that the measurement technique and data analysis are bilaterally equivalent and supports the reliability of the method. This is further borne out by an examination of the regional pattern in opposite hemispheres. Although the regional mean f1 values, expressed as percent of hemispheric mean, varied from a minimum of 85.7 occipitally to a maximum of 112.2 frontally, the means in comparable regions differed by less than 1.0%. These regional variations offi fit well with results previously obtained with the intra-arterial technique [13,14]. The possibility of the bilateral uniformity being due to cross-talk was considered. It is known that some degree of cross-talk exists not only between opposite pairs of detectors but also between adjacent detectors. However, independent phantom studies (to be reported separately) have shown only a 2436% counting rate contribution due to radioactivity in the opposite hemisphere. Moreover, in measurements on other patients flow values differing by a factor as much as 2:l betwen homologous pairs and by 3 : 1 between adjacent channels have been observed. In contrast, the marked variability in mean flow in a given individual from day to day is evidenced by the much lower correlation coefficients in the 20 repeated studies (Table 3). This variability is probably due in part to marked differences in the mental and physical state of the subjects [7,10,15], factors which today are only partly understood. However, the most significant aspect of the normal bilateral uniformity and the large day to day variations is that in patients with stroke or other focal neurologic disorders the significance of unilateral regional flow changes as a function of time should be preferably determined relative to the unaffected or “reference” hemisphere. This suggests the need for simultaneous bilateral flow measurements when any degree of cerebrovascular pathology is suspect. The significant CBF differences between the young normals and the generally older stroke patients is partly due to the normal aging process. A more dominant factor is probably the cerebrovascular pathology which will be discussed in forthcoming publications. The interpretation of clinical data would also be simplified if “normal” subjects in successive age groups were studied to establish more comparable regional and hemispheric reference values. The system is being expanded to a total of 24 information channels. The additional data analysis and display time (some 3 to 4 min) will have negligible effect on the total procedural time. The addition of an analog multiplexor with an A/D converter will enable us to include other signals (e.g. EEG epochs, arterial pressure, heart rate, expiratory COz, etc.) in the on-line data acquisition. It is also expected that the scope of the rCBF studies will be enlarged to include patients with brain death, pre-and-postcardiac pacemaker implantation, head trauma, and pre-and-post-neurosurgery. The possibility of using “‘Xenon in lieu of ’ “3Xenon is also being considered because of several potential advantages. It is not a beta emitter, and therefore has a lower dosimetry (1.5 mR/mCi/min. for “‘Xenon vs 5.1 for ‘33Xenon). The two gamma photo peaks of 203 and 173 KeV are above technetium so that appropriate energy discrimination would permit rCBF measurements to be made relatively soon after brain scans (assuming detector and amplifier dead time is sufficiently low). Its longer half-life (36 vs 5.2 days) would reduce the amount of gas, especially in the rebreathing system. The additional C.R.M.
1/2---F
156
EDWIN M. WILSONet al.
hemispheric cross-talk, i.e. counting from the contralateral hemisphere, because of the higher energy gamma should be relatively small (d* in muscle is 5 cm for “‘Xenon versus 3.9 cm for lJ3Xenon). The reduced efficiency of the crystals should be more than offset by the larger allowable concentrations. The potential advantages of ‘27Xenon are more than offset at present, however, due to its relative unavailability and high cost. SUMMARY This paper describes a computer based multidetector system which was developed for the measurement of regional cerebral blood flow (rCBF) by the 133Xenon inhalation technique. The computer portion of the system is characterized by on-line data acquisition, rapid data analysis and presentation of results (the total elapsed time from initial positioning of subject to generation of hard copy for 14 channels is less than 25 min). Special system features include programs which automatically determine end-tidal Xenon concentrations during the saturation and desaturation phases of the flow measurement and provide for automatic background subtraction. A special purpose counter digital multiplexor interface was developed which is controlled by two computer instructions. Data and results are output on a CRT terminal in alpha-numeric, graphical format with an attached hard copy unit, also used for program listings, etc. Typical output formats are included. The system also provi&s convenience in handling acutely ill patients to assure reproducible positioning for serial measurements and in administering the radioactive gas. Preliminary results are presented from 110 studies on 30 apparently healthy young volunteers and 40 studies on 19 patients with cerebra-vascular accidents. In the normal group single studies showed a significant regional variation in flow and weight parameters but a remarkable bilateral uniformity. In contrast, marked variability in mean flow for a given subject from day to day was observed, probably due to marked differences in the mental and physical state of the subjects. This bilateral uniformity and day to day variability suggests that in patients with stroke or other focal neurologic ‘disorders the significance of unilateral regional flow changes should be determined relative to the unaffected or “reference” hemisphere and supports the need for simultaneous bilateral measurements. The difference in blood flow of the fast compartment (fi) between the normals and the patients was highly significant (t-test, p < 0.001). Acknowledgement-The authors are indebted to Mr. L. N. LARKINfor engineering assistance during system development, and to Mr. A. V. WHITEfor technical assistance in the operation of the Cerebral Blood Flow Laboratory.
REFERENCES B. L. Mallett and N. Veall, Investigation of cerebral blood flow in hypertension using radioactive Xenon inhalation and extracranial recording. LMcet ii, 1081-1082 (1963). B. L. Mallett and N. VeaIl, The measurement of regional cerebral clearance rates in man using Xenon-133 inhalation and extracranial recording. Clin. Sci. 29, 179-191 (1%5). W. D. Obrist, H. K. Thompson, C. D. King and S. S. Wang, Determination of regional cerebral blood flow by inhalation of 133Xenon. Cir. Rex 3, 124-135 (1967). W. D. Obrist, H. K. Thompson, S. S. Wang and S. Cronquist, A simplified procedure for determining fast compartment rCBF by ‘33Xenon inhalation. In. Brain and Blood Flow (Ed. R. W. Ross-Russel). Pitman, London. 11-15 (1971). 5. N. A. Lassen, K. Hsedt-Rasmussen, S. C. Sorensen, E. Skinhej, S. Cronquist, B. Bodforss and D. H. Ingvar, Regional cerebral blood flow in man determined by Krypton *5. Neurology 13, 719-727 (1963). 6. K. Heedt-Rasmussen, E. Sveinsdottir and N. A. Lassen, Regional cerebral blood flow in man determined by intra-aerterial injection of radioactive inert gas. Circulation Res. 18, 237-247 (1966). I. J. Risberg, J. H. Halsey, E. L. Wills and E. M. Wilson, Hemispheric specialization in normal man studied by bilateral measurements of the regional cerebral blood flow. Brain 98, 511-524 (1975). 8. W. D. Obrist, H. K. Thompson, H. S. Wang and W. E. Wilkenson, Regional cerebral blood flow estimated by ‘33Xenon inhalation. Stroke 6, 245-256 (1975). 9. N. Veal1 and B. L. Mallett, The partition of trace amounts of Xenon between human blood and brain tissues at 37°C. Phys. Med. Biol. IO, 375-380 (1965). 10. J. Risberg, Z. Ali, E. M. Wilson, E. L. Wills and J. H. Halsey, Regional cerebral blood flow by ‘33Xenon inhalation. Stroke 6, 142-148 (1975).
Measurement of regional cerebral blood flow 11. S. C. Alexander, H. Wollman, P. J. Cohen, P. E. Chase and M. Behar, Cerebrovascular
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response to PaCOl during halothane anesthesia in man. J. appl. Physiol. 19, 561-565 (1964). M. K. Loken and G. S. Kush, Handling, uses, and radiation dosimetry of Xenon-133. In Med. Radionuclides: Radiation Dose and Eficts. (Eds. R. J. Cloutier, C. L. Edwards and W. S. Snyder) AEC Div. Tech. Info. Oak Ridge, Tn, pp. 253-270 (1970). I. M. S. Wilkinson, J. W. D. Bull, G. H. Duboulay, J. Marshall, R. W. Ross-Russell and L. Symon, Regional blood flow in the normal cerebral hemisphere. J. Neural. Neurosurg. Psych&. 32, 367-378 (1969). E. Sveinsdottir, P. Thorlof, J. Risberg, D. H. Ingvar and N. A. Lassen, Calculation of regional cerebral blood flow (rCBF): Initial-slope-index compared to height-over-total-area values. In Brain and Blood Flow: Proc. 4th Int. Symp. on the Regulation of Cerebral Blood Flow. London, p. 85 (1970). J. Risberg and D. H. Ingvar, Patterns of activation in the grey matter of the dominant hemisphere during memorization and reasoning. A study of regional cerebral blood flow changes during psychological testing in a group of neurologically normal patients. Brain %, 737-756 (1973). About the AII~~-ED~IN
M. WILSONreceived his B.S. degree in Electrical Engineering and in Business and Engineering Administration from the Massachussetts Institute of Technology and an Sc.D. in Biomedical Engineering from the University of Virginia in 1967. He has had industrial experience in the area of feedback control systems. His work at the U.A.B. has involved biomedical engineering applications in cardiology, particularly in blood flow measurements. More recently Dr. Wilson has been engaged in research in neurology with emphasis on monitoring patients with cerebrovascular accidents and experimental animal models of cerebral ischemia and infarction using mini-computers and special purpose electronic systems. He teaches courses in digital and analog computers and in medical instrumentation. Dr. Wilson is currently Associate Professor in the School of Engineering and holds joint appointments in the Department of Information Science and the Department of Neurology. About the Author-EDWARD L. WILLS received the B.S. and M.S. degrees from Auburn Univer-
sity and the Ph.D. in physics from the University of Virginia in 1968 with research at the Space Radiation Effects Laboratory synchrocyclotron. As a Research Associate and Assistant Professor at the University of Georgia he was engaged in the development of the UGA 5MV Van de Graalf facility and research in isobaric analog states. Dr. Wills joined the U.A.B. in 1973 where he is currently Assistant Professor in the Department of Physics and is involved with radioisotope techniques with the Department of Neurology. Dr. Wills is a member of the American Physical Society, Phi Kappa Phi, and Sigma Xi. A. RISEJIGreceived a Ph.D. in Psychology from the University of Lund, Sweden, in 1969, where for 10 years he has been interested in cerebral blood flow as an index of mental activity. He was Research Associate in the Department of Neurology at the University of Alabama Medical Center in Birmingham, Alabama 1973-1974. Dr. Risberg is Associate Professor of Psychology at the University Hospital, Lund, Sweden where he is director of the laboratory of neuropsychology.
About the Author-JmL
About the Author-JAr+ms H. HALSEY, JR., M.D. is a 1959 graduate of Yale University Medical School and had his specialty training in Neurology at the University of North Carolina. He is principally interested in development and application of new monitoring methods for clinical management of patients with stroke. Dr. Halsey is Professor and Chairman, Department of Neurology at the University of Alabama Medical Center in Birmingham, Alabama where is has been a faculty member since 1965. About the Author-J_aas
D. GERARDreceived his B.S. degree in mathematics from Birmingham Southern College in 1970. He is currently employed r&Systems Analyst in the Division of Biophysical Sciences, U.A.B. Medical Center engaged primarily in computer processing of exercise ECG data and continuous arrhythmia analysis. He is a member of the Association for Computer Machinery. P. MAY received her B.S. degree in mathematics from Spring Hill College in 1972 and her M.C.S. degree from Texas A & M University in 1973. During 1974, she held a joint appointment of instructor in the Department of Information Sciences and the Department of Neurology at the University of Alabama in Birmingham. Since October, 1974, she has been a part-time instructor and has been pursuing a Ph.D. degree in Information Sciences. She is currently developing her thesis topic in the area of data base equivalence. About the Author-Chmmm