George A. Taylor, MD * Billie L. Short, MD * L. Kyle Walker, MD * Richard J. Traystman, PhD
Intracranial Blood Flow: uantification with Duplex Doppler and Color Doppler Flow US' The authors compared changes in cerebral blood flow (CBF), determined by means of injection of radiolabeled microspheres, with Doppler blood flow measurements obtained simultaneously in the middle (n = 9) and anterior cerebral arteries (n = 3) in 12 newborn lambs. Doppler estimates of blood flow and mean blood flow velocity correlated well with changes in CBF. However, with changes in mean blood flow velocity, the degree of change in CBF tended to be underestimated. The resistive index correlated well with perfusion pressure but correlated weakly with cerebrovascular resistance and poorly with changes in CBF. Doppler blood flow estimates and mean blood flow velocities correlate well with changes in CBF and allow significant improvement in accuracy over instantaneous velocity or pulsatility measurements alone. Determination of absolute blood flow remains difficult due to systolic and diastolic differences in vessel diameter and intrinsic error in true diameter measurement with currently available color flow technology. Index terms: Cerebral blood vessels, flow dynamics, 17.92 * Cerebral blood vessels, US studies, 17.12984 * Ultrasound (US), Doppler studies, 17.12984 * Ultrasound (US), experimental, 17.12984
Radiology 1990; 176:231-236
cerebral blood flow (CBF) are thought to be a key factor in the development of ischemic or hemorrhagic lesions in the newborn brain (1,2). Thus, the development of an accurate noninvasive tool for repeated measurement of CBF in the newborn might be useful in understanding the pathophysiology and possible prevention of cerebrovascular injury. Transcutaneous Doppler ultrasound (US) has been used to investigate vascular flow patterns in a variety of conditions in the newborn (37), including those in infants undergoing extracorporeal membrane oxygenation (8,9). Most recently, Siebert et al (10) studied the role of the resistive index (RI) in the evaluation of increased intracranial pressure and reported a linear correlation between RI and intracranial pressure in dogs, as well as significant reductions in RI in newborns following ligation of a patent ductus arteriosus, tapping of subdural effusions, and ventricular tapping. Horgan et al (11) studied absolute blood flow velocities in asymptomatic preterm and term neonates. They found that both systolic and diastolic velocities increase, while RI decreases progressively with the age of the infant (11). These studies were based on the assumption that changes in the RI or instantaneous blood flow velocity may reflect changes in true cerebral blood flow. Sonesson and Herin (12) have shown that changes in mean blood flow velocity correlate well with changes in CBF, but the true change ABNORMALITIES in
' From the Russell H. Morgan Department of Radiology and the Departments of Pediatrics (G.A.T.) and Anesthesia/Critical Care (B.L.S., L.K.W., R.J.T.), The Johns Hopkins School of Medicine, 600 N Wolfe St, Baltimore, MD 21205 and the Department of Pediatrics, Childrens National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC (B.L.S.). Received November 14, 1989; revision requested December 29; final revision received February 26, 1990; accepted March 19. Supported in part by U.S. Public Health Service/ National Institutes of Health grant no. NS20020. Address reprint requests to G.A.T. c RSNA, 1990
in CBF can be significantly underestimated. In their study, about 55% of the actual change in CBF was predicted on the basis of blood flow velocity. They suggested that changes in the cross-sectional area of the vessel occur and allow more blood to flow through a vessel without a concomitant increase in velocity. This study was performed to evaluate the relationship between Doppler waveform measurements and CBF and to explore the possibility of obtaining reliable blood flow measurements with color Doppler US and duplex Doppler US in a newborn lamb model.
SUBJECTS AND METHODS Subjects Twelve newborn lambs of mixed breed, aged 1-7 days, were used as experimental subjects. The weight of the lambs ranged from 3.0 to 8.3 kg (mean, 5.2 kg).
Surgical Procedure The lambs were anesthetized with an initial bolus of pentobarbital (12-15 mg/ kg) before surgery, followed by drip infusion of pentobarbital (3 mg/kg/h) and pancuronium bromide (0.1 mg/kg) every 3-4 hours for the remainder of the experiment. The animals were then intubated and underwent mechanical ventilation by means of a pump respirator (Harvard Apparatus, Dover, Mass). Polyvinyl chloride catheters (Martech Medical Products, Harlysville, Pa) were placed in the right femoral artery for continuous blood pressure monitoring, the right femoral vein for administration of intravenous fluids and medications, and the left ventricle (via the right brachiocephalic artery) for injection of radiolabeled
Abbreviations: ANOVA
=
analysis of vari-
ance, CBF = cerebral blood flow, Pco2 = partial pressure of carbon dioxide, P02 = partial pressure of oxygen, RI = resistive index.
231
Table 1 Summary of Protocol A Used to Vary CBF in Five Lambs Arterial
60-Minute
Pressure (mm Hg)
Control
Po2 Pco2
Mean blood pressure
60 Minutes of
30 Minutes of
Period
120 Minutes of Hypocapnea/ Normoxia
Hypoxia/ Hypocapnea
Hypoxia/ Normocapnea
Normocapnea
86.6 I 8.3 35.0 1 1.4
112.0 i: 8.2 17.1 i 0.4*
46.8 I 19.1* 15.0 + 1.4*
33.8 i 2.0* 36.7 i 1.2
92.5 + 4.7 37.3 k 1.4
83.5 ± 2.8
75.7 k 2.6*
65.6 + 3.1*
59.2 i 3.3*
60.8 i 4.4*
30 Minutes of Normoxia/
Note.-Numbers represent means i standard errors of the means. ' Difference between baseline values and those denoted are significant (P < .05) by means of factorial ANOVA.
Figure 1. Branch of the lett middle cerebral artery in a 4-kg, 3-day-old lamb. Color calipers are positioned over the closest pixel at the edges of the vessel containing no flow information. Distance between calipers is used as vessel diameter estimate for volume flow calculations. Vessel diameter is 1.3 mm.
microspheres. Catheters were also placed in the left lingual artery for obtaining microsphere reference samples and in the sagittal sinus for pressure monitoring. The sagittal sinus was entered in the midline approximately 1 cm anterior to the la~nbdoid suture after the overlying calvaria was thinned with a surgical drill. A 1-cm burr hole for US access was made in the left parietal bone approximately 1 cm lateral to the midline and 1.5 cm anterior to the lambdoid suture.
Mean arterial blood, pulse, and sagittal sinus pressures were continuously monitored with a multichannel recorder (Gould Instruments, Ormand, Calif). At each study interval, arterial pH, partial pressure of carbon dioxide (Pco2), and partial pressure of oxygen (Po2) were measured at 39.5°C with the ABL 30 radiometer (Radiometer, Cleveland), and oxygen saturation and hemoglobin were measured with the OSM2 hemoximeter (Radiometer) calibrated for lamb's blood. Cerebral perfusion pressure (mean arterial blood pressure - mean sagittal sinus pressure) and cerebrovascular resistance (perfusion pressure/supratentorial CBF) were calculated at each interval (13). The animals were killed at the end of the experiment with an intravenous overdose of pentobarbital and saturated potassium chloride solution. Catheter placement was verified at autopsy, and the brain was removed for microsphere analysis.
CBF Measurements CBF was measured with the radiolabeled microsphere technique (14). We used microspheres measuring 15 Asm in diameter; labeled with indium-1 14, tin113, ruthenium-103, niobium-95, scandium-46, gadolinum-153; and suspended in a solution containing approximately 1.4 X 106 microspheres (DuPont, Boston). The
232 * Radiology
Table 2 Summary of Protocol B Used in Five Lambs to Vary CBF Arterial Pressure (mm Hg)
P02
Pco2 Mean blood pressure
60-Minute Control Period
60 Minutes of Hypoxia/ Normocapnea
120 Minutes of Hypoxia/ Hypocapnea
30 Minutes of Hypoxia/ Normocapnea
30 Minutes of Normoxia/ Normocapnea
103.7 I 8.7 36.5 + 1.7
32.0 * 2.2* 34.6 i 0.6
35.5 I 2.3* 18.6 + 1.6*
27.6 1 2.2* 36.1 ± 2.0
81.0 i 2.9* 35.0 * 1.0
82.2 :k 3.9
75.1 ± 2.4
71.9 + 2.3*
65.7 * 2.3*
60.0 i:
2.9*
Note.-Numbers represent means i standard errors of the means. * Difference between baseline values and those denoted are significant (P < .05) by means of factorial ANOVA.
Table 3 Summary of Protocol C Used to Vary CBF in Two Lambs Drug and
60-Minute
Arterial Pressure (mm Hg)
Control Period
30 Minutes of
Hypotension
30 Minutes with Pressor
30 Minutes without Pressor
... ... ...
83.0 36.0 32.0
83.0 37.5 103.5
84.0 35.0 65.0
19.0
20.0 95.0 80.0
23.0 118.0 25.0
Phenylephrine P02 Pco2 Mean blood pressure Epinephrine P02 Pco2 Mean blood pressure
33.0 84.0
94.0
60.0
25.0
Note.-Numbers are means.
microspheres were chosen in random order, and 0.4 mL was injected for 45 seconds into the left ventricular catheter. A reference blood sample was simultaneously withdrawn from the lingual artery at a rate of 2.47 mL/min for 1 minute with a calibrated syringe (Harvard Apparatus). Tissue and reference blood samples were counted in a deep-well gamma counter (Packard Instruments, Downers Grove, Ill). The energy windows used for In-1 14, Sn-1 13, Ru-103, Nb-95, Sc-46, and
Gd-153 were 174-230, 360-440, 450-560, 690-820, 830-1,200, and 70-174 keV, respectively. Regional blood flow was calculated as Qreg = Creg * Qref/Cref * 100, where Qreg is regional blood flow (milliliters per minute per 100 g of brain tissue), Qref is the reference blood withdrawal rate (milliliters per minute), Ce9 is the number of counts per gram of tissue, and Cref is the number of counts in the reference blood samples. Blood flows were determined for the whole brain, right and left hemispheres (supratentorial blood
flow), brain stem, caudate nucleus, and cerebellum.
Doppler Measurements A computerized color flow imager, equipped with a 7.0-MHz linear transducer, was used for gray-scale US and color Doppler flow US (Acuson 128; Mountain View, Calif). The transducer uses a broad band response to create the gray-scale image at a frequency centered at 7.0 MHz and the color Doppler image at a frequency centered at 5.0 MHz. A branch of the middle (n = 9) or anterior cerebral artery (n = 3) was identified, and the transducer was fixed into position with a mechanical holder. The image was electronically magnified, and the color sensitivity volume was restricted to a maximum degree to maximize the color sensitivity and frame rate. The color persistence and filter were set at the lowest settings, and color gain was kept at approximately midpoint. Under these conditions, the esti-
July 1990
% Chaigp hi 1 5C Doppler Blood
FlowI
0
20
40
60
80
100
120
140
Suprutentorlal CBF (mnIO0 gm/min)
3. 2. Figures 2, 3. (2) Change in calculated Doppler blood flow versus change in supratentorial cerebral blood flow, calculated as the percentage of change from baseline measurements. Correlation coefficients and significance values for individual animals (LI-L12) are to the right of the chart. Bold line denotes the mean regression line for the entire group (slope of regression line, y = 1.17x - 6.56; r = .88, P = .0001). (3) Change in calculated Doppler blood flow versus change in supratentorial cerebral blood flow. Correlation coefficients and significance values for individual animals (L1-L12) are to the right of the chart. Bold line denotes the mean regression line for the entire group (slope of regression line, y = 0.13x + 6.54; r = .42, P = .001).
mated pixel size is 0.3 mm, and the resolution of caliper measurements is 0.1 mm (Hayes A, Acuson; oral communication; 1990).
Diameter Estimates Vessel walls could not be reliably detected with gray-scale US alone. We therefore attempted to use color Doppler information to estimate vessel diameter. Twenty to 30 seconds of flow were imaged in real time, stored in cine mode, and reviewed. Electronic calipers that display the mean frequency shift of a selected pixel were placed over the closest pixel at the edges of the vessel containing no flow information. The distance between these calipers was used to estimate the diameter of the vessel (Fig 1). Color Doppler imaging algorithms are proprietary information but are usually designed to depict the color hue proportional to the mean velocity of flow within the interrogated pixel. If a pixel is only partly overlying a vessel lumen, the entire pixel will be depicted as containing flow. The accuracy of these measurements was further limited by the relatively large pixel size determined with the lower frequency (5 MHz) used to create the color image. Thus, it is likely that the true internal diameter of the selected vessel is overestimated with this technique. Despite the presence of flow during diastole, as determined with spectral analysis, color information was often absent during diastole. Therefore, vessel diameters were obtained only during peak systole. Because of the twofold limitations of current color Doppler technology and small vessel size, we did not expect to obtain accurate measurements of absolute vessel diameter but rather were interested in evaluating color Doppler US as a tool to detect relative changes in vessel diameter with perturbations in CBF. At least 10 diameter mea-
Volume 176 * Number 1
surements were made at each sampling period and were averaged. The mean diameter was used for calculations of the volume of blood flow (hereafter referred to as volume flow).
Spectral Analysis and Blood Flow Determinations
A velocity spectrum containing at least 10 cardiac cycles was fixed on the display screen. An on-board spectrum analyzer was used to calculate the mean blood flow velocity averaged over time. This was accomplished by placing electronic calipers at each end of the spectrum and measuring the average of all the instantaneous mean velocities over this time interval (approximately 3.5 seconds). This procedure was repeated at least five times at each experimental interval. A 1.0 X 1.5-mm cylindrical sample volume was used, and the angle of insonation was held at 15°-45°. The computed velocity was based on the angle measured on the image. A 125-Hz high-pass filter (lowest setting) was used for all measurements. Volume flow (Doppler blood flow in milliliters per minute) was estimated with the formula (7rr2 60 sec * mean velocity). RI was calculated at each interval by means of the Pourcelot formula modified by Bada et al (15): ([systolic velocity - diastolic velocity] /systolic velocity). -
Experimental Protocols Three separate experimental conditions were used to vary CBF. Protocol A (five lambs) consisted of a 60-minute control period, followed by 120 minutes of hypocapnea and normoxia, 60 minutes of hypoxia and hypocapnea, 30 minutes of hypoxia and normocapnea, and 30 minutes of normoxia and normocapnea. In protocol B (five lambs), the order of the first two experimental conditions in protocol A
was reversed (ie, 60 minutes of hypoxia and normocapnea, followed by 120 minutes of hypoxia and hypocapnea, etc). In protocol C, two hypotensive animals were treated with a constant infusion of either phenylephrine or epinephrine for 30 minutes, followed by a measurement obtained 30 minutes after discontinuation of either drug. Although the individual effects of hypoxia or hypocapnea on CBF were difficult to discern with these protocols, we thought they approximated the clinical conditions most often experienced in infants with severe respiratory distress. Doppler measurements of blood flow velocity, RI, and vessel diameter were obtained simultaneously with injections of radiolabeled microspheres during each
experimental condition.
Data Analysis Doppler measurements of diameter, systolic velocity, diastolic velocity, mean blood flow velocity, RI, and Doppler blood flow were correlated with CBF determined by means of microsphere injection. Both absolute and relative changes in CBF (expressed as the percentage of change from baseline values) were used in these analyses. Correlations were tested by means of simple and multiple linear regression models. Differences in physiologic variables, such as arterial Po2, Pco2, and mean blood pressure during different experimental conditions, were analyzed by using a factorial analysis of variance (ANOVA).
RESULTS A summary of the protocols and mean arterial blood pressure, Pa2, and PCo2 values during each condition are listed in Tables 1-3.
Radiology * 233
Doppler Blood Flow versus CBF A wide range of CBF was produced with manipulation of arterial blood gases and blood pressure. CBF varied from 17.7 to 135.7 mL/min per 100 g of brain tissue (relative change in CBF, -70% to 136% from baseline values). Relative Doppler blood flow varied over a similar range (-67% to 157% change from baseline values) and correlated well with changes in CBF both within individual animals and for the entire group (Fig 2; y = 1.17x 6.56, r = .88, P = .0001). The relationship between relative Doppler blood flow and CBF was further corroborated by comparing changes in CBF to changes in mean blood flow velocity and diameter by means of multiple linear regression. This model assumes that the variables predict more information collectively than each could predict independently of the other. The change in both diameter and mean blood flow velocity contributed significantly to predicting change in CBF (regression coefficient = 0.61, P = .0001 for change in mean blood flow velocity; regression coefficient = 1.29, P = .0001 for change in vessel diameter; r = .87, P = .0001 for the entire model). Although absolute values for Doppler blood flow correlated well with absolute CBF in individual lambs, the correlation was weak between absolute values for Doppler blood flow and absolute CBF for the whole group (Fig 3; r = .42, P = .001).
3 50 Figure 4. Change > in mean blood flow 3 00 velocity versus change in supratenChn 2 torial cerebral blood Adog flow calculated as Bbod 200 the percentage of voloctty change from baseline measurements. Correlation coeffiI cients and signifi50 cance values for individual animals (LI-L12) are to the right of the chart. -so Bold line denotes the mean regres.10 0 sion line for the en0 25 50 .75 .50 .25 'hang. tire group (slope of In CBF regression line, y = 0.94x - 3.07; r = .79, P = .0001).
Vessel Diameter versus CBF
In general, mean vessel diameter tended to enlarge as CBF increased (Fig 8; r = .49, P = .0001). One exception to this observation was a hypotensive animal treated with intravenous phenylephrine, a potent vasoconstrictor. As CBF increased with infusion of phenylephrine, mean blood flow velocity and calculated Doppler blood flow increased concomitantly, while mean vessel diameter decreased by 19.5%. These pheFlow Velocity versus CBF nomena were not observed in the Changes in mean blood flow veloc- second hypotensive animal treated with epinephrine. No relationship ity alone also correlated well with was found between the change in obchanges in CBF (Fig 4; y = 0.94x served diameter and change in mean 3.07, r = .79, P = .0001), but the deblood flow velocity (r = .16, P > .2). gree of change in CBF tended to be Thus, it seems unlikely that an inunderestimated with these data. As shown in Figure 4, the slopes of most crease in estimated diameter was artiof the individual regression lines ficially caused by an increase in were below the line of identity. Abmean blood flow velocity detected at solute values for mean blood flow ve- or near the vessel edge. locity correlated poorly with CBF (r = .26, P 2 .2). Instantaneous peak DISCUSSION systolic and end-diastolic velocity Our data show that Doppler estimeasurements both showed only a of blood flow and mean blood mates r = weak correlation with CBF (Fig 5; correlate well with relflow velocity .46, P = .01, and r = .41, P = .02, reand that other frequently ative CBF spectively). used Doppler measurements, such as systolic and diastolic velocities and RI versus CBF RI, are only weak predictors of Increases in RI were principally change in CBF. due to a decrease in diastolic velocity, The measurement of mean blood with relatively little change occurflow velocity is relatively simple ring in systolic velocity (Fig 6). Alwith the use of color Doppler flow though RI correlated well with US for vessel localization, and the changes in cerebral perfusion presclose relationship between changes sure (r = .82, P = .0001), it correlated in mean blood flow velocity and only weakly with cerebrovascular re- changes in relative blood flow has sistance (Fig 7; r = .42, P = .02) and been demonstrated in several in vitro poorly with both absolute and rela(16,17), human (18,19), and animal tive values for CBF (r = .11, r = .17, (17,20) experiments. Our findings respectively; P > .2). There was no confirm this relationship and suggest that changes in mean blood flow vesignificant change in heart rate during each experimental interval. locity can probably be used to moni-
234 . Radiology
75 100 125 150 175
tor changes in relative CBF under most experimental circumstances. However, there are situations in which vessel diameter significantly changes (eg, during pharmacologic vasoconstriction), and the innacuracy of mean blood flow velocity measurements then increases. We confirm the prior findings by Sonesson and Herin (12) that suggested that changes in mean blood flow velocity tend to underestimate the true change in CBF. In the current study, the slope of the aggregate regression line comparing change in mean blood flow velocity and change in CBF is close to the line of identity (y = 0.94x - 3.07); however, most individual regression lines underestimate change in flow by approximately 50% (Fig 4). Measurements of peak systolic and end-diastolic velocities showed general trends that correlated with changes in CBF. However, the degree of variability was broad, and the value of these measures in predicting change in CBF was limited. Several authors have shown that accurate measurements of absolute flow are possible in vitro and in larger vessels (3.7-8.0-mm arteries) if the Doppler frequency shift and the diameter of the vessel are known (2123). Application of these techniques to the intracranial circulation has been difficult because of small vessel size and subsequent problems in determining vessel orientation and internal diameter when only gray-scale US is used. In this study, we used color flow imaging in an attempt to address these systematic limitations. Colorcoded flow information was helpful in obtaining accurate placement and sizing of the sample volume, as well as in determining the angle of the in-
July 1990
I 0.
70
*0
00
0 Dhm.0.
30
Voloo~y 0
0
40
20
0
S.
a. 0
20
I
ol.0
s 100 I50 200 % Chwop In CSF
50
0
210
350
300
400
-
500
050
I
100 100 200 % Chongo in CBF
200
200
250
400
b.
a.
Figure S. (a) Systolic velocity versus change in supratentorial blood flow (slope of regression line, y = 0.19x + 30.33; r = .59, p = .0004). (b) Diastolic velocity versus change in supratentorial blood flow (slope of regression line, y = 0.1x + 14.32; r = .48, p = .0063).
900
a00
0
70O FN 60a
0~~~~
0
ly unchanged, while diastolic velocities were lower with increasing RI values. However, equivalent changes in systolic and diastolic velocities can be present without affecting the RI (20,26). More important, many factors other than cerebrovascular resistance may affect the RI in an intracranial vessel. These include the presence of a patent ductus arteriosus and changes in heart rate and cardiac output, as well as the use of different high-pass filter settings while spectra are being obtained (27,28). Our data confirm that the RI is not a good predictor of changes in CBF and is only weakly related to cerebrovascular resistance. We conclude that relatively accurate estimates of change in intracranial blood flow are possible with duplex Doppler and color Doppler flow imaging and that studies in which instantaneous velocity measurements
00
~~O
40
0
SW
30 2 01 S00
40
0
70
00
0
1 00
00
1 10
1 20
1 30
14 0
Systoic Veotooty (on~feoc.)
Vaboooy foovomo)
Obsoolo
b.
a.
Figure
(a) RI
6.
peak systolic .55 velocity (r
blood flow
versus
diastolic blood flow
P
=
=
velocity (r
.05 P >
=
2).
RI
versus
end-
and the RI are used to assess changes in the cerebral circulation should be interpreted with caution. Further refinements in instrumentation and the development of small vessel flow phantoms may allow continued improvements in the accuracy of US flow measurements. U
.0001).
Acknowledgments:
We thank Deborah Flock,
Karen Bender, MD, and Maurizio Solca, MD,
cident beam to the direction of flow.
Although ume
absolute
of vol-
measures
flow correlated well with abso-
lute CBF in individual animals, abso-
probably resulted from several factors: changes in vessel diameter over time during the cardiac cycle, as well as an
overestimation of diameter due
to inclusion
of
may have contributed to inaccuracies
pixels containing color that were partly outside the vessel lumen; limited spatial resolution of color flow imaging at 5 MHz; and small vessel size. Yet, despite these
in blood flow determination with
limitations, estimates of vessel diam-
US. These include
eter
only pooled data
lute blood flow correlated
weakly with CBF when were analyzed. Several potential sources
of
error
for technical support.
References 1.
Volpe JJ.
the cross-sectional
ing
provided ing improved
in estimat-
area
of the
vessel, the angle of the incident beam, and the uniformity of insonation
across
Volpe Ji,
phy
were so
in the newborn: extensive
ple
volume size and could be
sam-
easily
rated
by
was
the presence of
a
corrobo-
is
unlikely
cation
the
or
angle
imaging,
it
inaccuracies in
of incidence
determining
signifiattempted
were
cant sources of error. We
changes use
of
The
Bashiru M, Russell J, Bada HS, Menke JA,
It is
to reduce errors in the determination
Doppler
of cross-sectional
minimizes the effect of
area
by repeating
the diameter measurements several times an
during
each interval and
using
average value for volume flow cal-
culations. Yet, estimation of the
cross-sectional
area
of the vessel
re-
likely source of ranthis study. Inaccuracies
mains the most
dom
error
in
in volume flow estimates with US
Volume 176 s Number 1Ra
5.
an
an
Volpe JJ.
Decrease in
hydrocephalus.
Bada HS, Miller
pulsatile
pulsatile
Pediatrics 1982;
JE, Menke JA,
et al.
In-
flow measurements in neonatal
intraventricular
probe place-
hemorrhage. J
Pediatr
1982; 100:291-296. 7.
Ahmann PA,
8.
Taylor GA, Short BL, Glass P, Ichord R. Cerebral hemodynamics in infants undergoing extracorporeal membrane oxygenation. Radiology 1988; 168:163-167.
indirect measurement of
velocity. Its utility is based on the assumption that changes in resistance affect diastolic flow velocity more than systolic velocity. In this study, systolic velocities remained relative-
in the prema-
tracranial pressure and cerebral arterial
measurement because it
The RI is
Hill A,
fantile
ment and can be
without
hemorrhage
infant. Pediatrics 1982; 69:144-149.
69:4-7.
attractive
easily obtained velocity signal calibration.
Volpe JJ. Relationpneumothorax to occurrence of in-
flow in the anterior cerebral artery in in-
indicator of cerebral
(5,11,25).
of
traventricular
6.
blood flow
Noninvasive detec-
Hill A, Perlman JM,
ship
multiple regression model. RI has been used by several as an
and hemor-
Bruit 1980; 4:619-623. 4.
a
authors
hemorrhage
intracerebral involvement. Pediat-
tion of neonatal cerebrovascular disease.
significant
and relative CBF with the
impair-
cerebral blood flow with
Miles R, Sumner D.
correlation between diameter
that nonuniform insonifi-
regional
JM,
tomogra-
rics 1983; 72:589-601.
3.
ture
identified with color flow
of
rhagic
velocity alone. The provided
with diameter estimates
study
small in relation to the
blood flow
mean
over
Positron emission
intraventricular
imag-
the accuracy of relative
volume flow measurements
Herscovitch P. Perlman
Raichle ME.
additional information
the vessel (24). Because
the vessels insonated in this
with color flow
inju-
153:243-251. 2.
ment
errors
Current concepts of brain
ry in the premature infant. AJR 1989;
Dykes FD, Lazzara A, et al. Relationship between pressure passivity and subependymal /intraventricular hemorrhage as assessed by pulsed Doppler ultrasound. Pediatrics 1983; 72:665-669.
Radiology,* 235
1
201
iol0
1 1
1 00
90
RI
% Change In
80
Vesx Diameter
0
70
-1
a 0 ..
5 0,
*
*@00 * 00
40
3 0 .1
.
.25
2.25 1 1.25 1 .5 1 .75 2 .75 Cerbrovascular ResIetance (mm Kglml/100 gm/ min)
.5
2.5
2.75
7. Figures
c
0
60
3
-75 -50 -25
25 50 0 % Chanp In CSF
75 100 125 150 175
8.
7,
(7) RI
versus
cerebrovascular resistance
(slope
of
regression line,
y
= -8.96x +
66.78;
r
=
.42, P
=
.02). (8) Change
in
mean ves-
sel diameter versus change in CBF, calculated as the percentage of change from baseline measurements. Correlation coefficients and significance values for individual animals (L1-L12) are to the right of the chart. Bold line denotes the mean regression line for the entire group (slope of regression line, y = 0.14x - 4.82; r .49, P = .0001). Arrow = individual regression line for hypotensive animal treated with intravenous phenylephrine. =
9. Mitchell DG, Merton D, Desai H, et al. Neonatal brain: color Doppler imaging. II. Altered flow patterns from extracorporeal membrane oxygenation. Radiology 1988; 167:307-310. 10. Seibert JJ, McCowan TC, Chadduck WM, et al. Duplex pulsed Doppler US versus intracranial pressure in the neonate: clinical and experimental studies. Radiology 1989; 171:155-159. 11. Horgan JG, Rumack CM, Hay T, MancoJohnson ML, Merenstein GB, Esola C. Absolute intracranial blood-flow velocities evaluated by duplex Doppler sonography in asymptomatic preterm and term neonates. AJR 1989; 152:1059-1064. 12. Sonesson SE, Herin P. Intracranial arterial blood flow velocity and brain blood flow during hypocarbia and hypercarbia in newborn lambs: a validation of rangegated Doppler ultrasound flow velocimetry. Pediatr Res 1988; 24:423-426. 13. Donegan JH, Traystman RJ, Koehler RC, Jones MD, Rogers MC. Cerebrovascular hypoxic and autoregulatory responses during reduced brain metabolism. Am J Physiol 1985; 18:421-429. 14. Heyman MA, Payne BD, Hoffman JIE, Rudolph AM. Blood flow measurements with radionuclide-labeled particles. Prog Cardiovasc Dis 1977; 20:55-77. 15. Bada HS, Miller JE, Menke JA, et al. Intracranial pressure and cerebral arterial
236 Radiology
16.
17.
18.
19.
20.
21.
pulsatile flow measurements in neonatal intraventricular hemorrhage. J Pediatr 1982; 100:291-296. Lundell BP, Lindstrom DP, Arnold TG. Neonatal cerebral blood flow velocity. I. An in vitro validation of the pulsed Doppler technique. Acta Pediatr Scand 1984; 73:810-815. Batton DG, Hellmann J, Hernandez MJ, Maisels MJ. Regional cerebral blood flow, cerebral blood velocity, and pulsatility index in newborn dogs. Pediatr Res 1983; 17:908-912. Rosenkrantz TS, Oh W. Cerebral blood flow velocity in infants with polycythemia and hyperviscosity: effects of partial exchange transfusion with Plasmanate. J Pediatr 1982; 101:94-98. Greisen G, Johansen K, Ellison PH, Fredriksen PS, Mali J, Friis-Hansen B. Cerebral blood flow in the newborn infant: comparison of Doppler ultrasound and 133-xenon clearance. J Pediatr 1984; 104:411-418. Hansen NB, Stonestreet BS, Rosenkrantz TS, Oh W. Validity of Doppler measurement of anterior cerebral artery blood flow velocity: correlation with brain blood flow in piglets. Pediatrics 1983; 72:526-531. Brody WR, Meindl JD. Theoretical analysis of the CW Doppler ultrasonic flowmeter. IEEE Trans Biomed Eng 1974; 21: 183-192.
22. Walter JP, McGahan JP, Lantz BMT. Absolute flow measurement using pulsed Doppler US. Radiology 1986; 159:545-548. 23. Loftus CM, Silvidi JA, Becker JA, Miller BV, Bernstein DD. Correlation of experimental rCBF determinations in goats with flow measurements from a Doppler-modified carotid artery shunt. J Ultrasound Med 1989; 8:7-13. 24. Gill RW. Measurement of blood flow by ultrasound: accuracy and sources of error. Ultrasound Med Biol 1985; 2:625-641. 25. Grant EG, White EM, Schellinger D, Choyke PL, Sarcone AL. Cranial duplex sonography of the infant. Radiology 1987; 163:177-185. 26. Rosenberg AA, Narayanan V, Jones MD. Comparison of anterior cerebral artery blood flow velocity an cerebral blood flow during hypoxia. Pediatr Res 1985; 19:6770.
27. Perlman JM, Hill A, Volpe JJ. The effect of patent ductus arteriosus on flow velocity in the anterior cerebral arteries: ductal steal in the premature infant. J Pediatr 1981; 99:767-771.
28. Taylor GA, Martin G, Short BL. Cardiac determinants of cerebral blood flow during ECMO. Invest Radiol 1989; 24:511516.
July 1990
Intracranial Blood Flow: uantification with Duplex Doppler and Color Doppler Flow US' The authors compared changes in cerebral blood flow (CBF), determined by means of injection of radiolabeled microspheres, with Doppler blood flow measurements obtained simultaneously in the middle (n = 9) and anterior cerebral arteries (n = 3) in 12 newborn lambs. Doppler estimates of blood flow and mean blood flow velocity correlated well with changes in CBF. However, with changes in mean blood flow velocity, the degree of change in CBF tended to be underestimated. The resistive index correlated well with perfusion pressure but correlated weakly with cerebrovascular resistance and poorly with changes in CBF. Doppler blood flow estimates and mean blood flow velocities correlate well with changes in CBF and allow significant improvement in accuracy over instantaneous velocity or pulsatility measurements alone. Determination of absolute blood flow remains difficult due to systolic and diastolic differences in vessel diameter and intrinsic error in true diameter measurement with currently available color flow technology. Index terms: Cerebral blood vessels, flow dynamics, 17.92 * Cerebral blood vessels, US studies, 17.12984 * Ultrasound (US), Doppler studies, 17.12984 * Ultrasound (US), experimental, 17.12984
Radiology 1990; 176:231-236
cerebral blood flow (CBF) are thought to be a key factor in the development of ischemic or hemorrhagic lesions in the newborn brain (1,2). Thus, the development of an accurate noninvasive tool for repeated measurement of CBF in the newborn might be useful in understanding the pathophysiology and possible prevention of cerebrovascular injury. Transcutaneous Doppler ultrasound (US) has been used to investigate vascular flow patterns in a variety of conditions in the newborn (37), including those in infants undergoing extracorporeal membrane oxygenation (8,9). Most recently, Siebert et al (10) studied the role of the resistive index (RI) in the evaluation of increased intracranial pressure and reported a linear correlation between RI and intracranial pressure in dogs, as well as significant reductions in RI in newborns following ligation of a patent ductus arteriosus, tapping of subdural effusions, and ventricular tapping. Horgan et al (11) studied absolute blood flow velocities in asymptomatic preterm and term neonates. They found that both systolic and diastolic velocities increase, while RI decreases progressively with the age of the infant (11). These studies were based on the assumption that changes in the RI or instantaneous blood flow velocity may reflect changes in true cerebral blood flow. Sonesson and Herin (12) have shown that changes in mean blood flow velocity correlate well with changes in CBF, but the true change ABNORMALITIES in
' From the Russell H. Morgan Department of Radiology and the Departments of Pediatrics (G.A.T.) and Anesthesia/Critical Care (B.L.S., L.K.W., R.J.T.), The Johns Hopkins School of Medicine, 600 N Wolfe St, Baltimore, MD 21205 and the Department of Pediatrics, Childrens National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC (B.L.S.). Received November 14, 1989; revision requested December 29; final revision received February 26, 1990; accepted March 19. Supported in part by U.S. Public Health Service/ National Institutes of Health grant no. NS20020. Address reprint requests to G.A.T. c RSNA, 1990
in CBF can be significantly underestimated. In their study, about 55% of the actual change in CBF was predicted on the basis of blood flow velocity. They suggested that changes in the cross-sectional area of the vessel occur and allow more blood to flow through a vessel without a concomitant increase in velocity. This study was performed to evaluate the relationship between Doppler waveform measurements and CBF and to explore the possibility of obtaining reliable blood flow measurements with color Doppler US and duplex Doppler US in a newborn lamb model.
SUBJECTS AND METHODS Subjects Twelve newborn lambs of mixed breed, aged 1-7 days, were used as experimental subjects. The weight of the lambs ranged from 3.0 to 8.3 kg (mean, 5.2 kg).
Surgical Procedure The lambs were anesthetized with an initial bolus of pentobarbital (12-15 mg/ kg) before surgery, followed by drip infusion of pentobarbital (3 mg/kg/h) and pancuronium bromide (0.1 mg/kg) every 3-4 hours for the remainder of the experiment. The animals were then intubated and underwent mechanical ventilation by means of a pump respirator (Harvard Apparatus, Dover, Mass). Polyvinyl chloride catheters (Martech Medical Products, Harlysville, Pa) were placed in the right femoral artery for continuous blood pressure monitoring, the right femoral vein for administration of intravenous fluids and medications, and the left ventricle (via the right brachiocephalic artery) for injection of radiolabeled
Abbreviations: ANOVA
=
analysis of vari-
ance, CBF = cerebral blood flow, Pco2 = partial pressure of carbon dioxide, P02 = partial pressure of oxygen, RI = resistive index.
231
Table 1 Summary of Protocol A Used to Vary CBF in Five Lambs Arterial
60-Minute
Pressure (mm Hg)
Control
Po2 Pco2
Mean blood pressure
60 Minutes of
30 Minutes of
Period
120 Minutes of Hypocapnea/ Normoxia
Hypoxia/ Hypocapnea
Hypoxia/ Normocapnea
Normocapnea
86.6 I 8.3 35.0 1 1.4
112.0 i: 8.2 17.1 i 0.4*
46.8 I 19.1* 15.0 + 1.4*
33.8 i 2.0* 36.7 i 1.2
92.5 + 4.7 37.3 k 1.4
83.5 ± 2.8
75.7 k 2.6*
65.6 + 3.1*
59.2 i 3.3*
60.8 i 4.4*
30 Minutes of Normoxia/
Note.-Numbers represent means i standard errors of the means. ' Difference between baseline values and those denoted are significant (P < .05) by means of factorial ANOVA.
Figure 1. Branch of the lett middle cerebral artery in a 4-kg, 3-day-old lamb. Color calipers are positioned over the closest pixel at the edges of the vessel containing no flow information. Distance between calipers is used as vessel diameter estimate for volume flow calculations. Vessel diameter is 1.3 mm.
microspheres. Catheters were also placed in the left lingual artery for obtaining microsphere reference samples and in the sagittal sinus for pressure monitoring. The sagittal sinus was entered in the midline approximately 1 cm anterior to the la~nbdoid suture after the overlying calvaria was thinned with a surgical drill. A 1-cm burr hole for US access was made in the left parietal bone approximately 1 cm lateral to the midline and 1.5 cm anterior to the lambdoid suture.
Mean arterial blood, pulse, and sagittal sinus pressures were continuously monitored with a multichannel recorder (Gould Instruments, Ormand, Calif). At each study interval, arterial pH, partial pressure of carbon dioxide (Pco2), and partial pressure of oxygen (Po2) were measured at 39.5°C with the ABL 30 radiometer (Radiometer, Cleveland), and oxygen saturation and hemoglobin were measured with the OSM2 hemoximeter (Radiometer) calibrated for lamb's blood. Cerebral perfusion pressure (mean arterial blood pressure - mean sagittal sinus pressure) and cerebrovascular resistance (perfusion pressure/supratentorial CBF) were calculated at each interval (13). The animals were killed at the end of the experiment with an intravenous overdose of pentobarbital and saturated potassium chloride solution. Catheter placement was verified at autopsy, and the brain was removed for microsphere analysis.
CBF Measurements CBF was measured with the radiolabeled microsphere technique (14). We used microspheres measuring 15 Asm in diameter; labeled with indium-1 14, tin113, ruthenium-103, niobium-95, scandium-46, gadolinum-153; and suspended in a solution containing approximately 1.4 X 106 microspheres (DuPont, Boston). The
232 * Radiology
Table 2 Summary of Protocol B Used in Five Lambs to Vary CBF Arterial Pressure (mm Hg)
P02
Pco2 Mean blood pressure
60-Minute Control Period
60 Minutes of Hypoxia/ Normocapnea
120 Minutes of Hypoxia/ Hypocapnea
30 Minutes of Hypoxia/ Normocapnea
30 Minutes of Normoxia/ Normocapnea
103.7 I 8.7 36.5 + 1.7
32.0 * 2.2* 34.6 i 0.6
35.5 I 2.3* 18.6 + 1.6*
27.6 1 2.2* 36.1 ± 2.0
81.0 i 2.9* 35.0 * 1.0
82.2 :k 3.9
75.1 ± 2.4
71.9 + 2.3*
65.7 * 2.3*
60.0 i:
2.9*
Note.-Numbers represent means i standard errors of the means. * Difference between baseline values and those denoted are significant (P < .05) by means of factorial ANOVA.
Table 3 Summary of Protocol C Used to Vary CBF in Two Lambs Drug and
60-Minute
Arterial Pressure (mm Hg)
Control Period
30 Minutes of
Hypotension
30 Minutes with Pressor
30 Minutes without Pressor
... ... ...
83.0 36.0 32.0
83.0 37.5 103.5
84.0 35.0 65.0
19.0
20.0 95.0 80.0
23.0 118.0 25.0
Phenylephrine P02 Pco2 Mean blood pressure Epinephrine P02 Pco2 Mean blood pressure
33.0 84.0
94.0
60.0
25.0
Note.-Numbers are means.
microspheres were chosen in random order, and 0.4 mL was injected for 45 seconds into the left ventricular catheter. A reference blood sample was simultaneously withdrawn from the lingual artery at a rate of 2.47 mL/min for 1 minute with a calibrated syringe (Harvard Apparatus). Tissue and reference blood samples were counted in a deep-well gamma counter (Packard Instruments, Downers Grove, Ill). The energy windows used for In-1 14, Sn-1 13, Ru-103, Nb-95, Sc-46, and
Gd-153 were 174-230, 360-440, 450-560, 690-820, 830-1,200, and 70-174 keV, respectively. Regional blood flow was calculated as Qreg = Creg * Qref/Cref * 100, where Qreg is regional blood flow (milliliters per minute per 100 g of brain tissue), Qref is the reference blood withdrawal rate (milliliters per minute), Ce9 is the number of counts per gram of tissue, and Cref is the number of counts in the reference blood samples. Blood flows were determined for the whole brain, right and left hemispheres (supratentorial blood
flow), brain stem, caudate nucleus, and cerebellum.
Doppler Measurements A computerized color flow imager, equipped with a 7.0-MHz linear transducer, was used for gray-scale US and color Doppler flow US (Acuson 128; Mountain View, Calif). The transducer uses a broad band response to create the gray-scale image at a frequency centered at 7.0 MHz and the color Doppler image at a frequency centered at 5.0 MHz. A branch of the middle (n = 9) or anterior cerebral artery (n = 3) was identified, and the transducer was fixed into position with a mechanical holder. The image was electronically magnified, and the color sensitivity volume was restricted to a maximum degree to maximize the color sensitivity and frame rate. The color persistence and filter were set at the lowest settings, and color gain was kept at approximately midpoint. Under these conditions, the esti-
July 1990
% Chaigp hi 1 5C Doppler Blood
FlowI
0
20
40
60
80
100
120
140
Suprutentorlal CBF (mnIO0 gm/min)
3. 2. Figures 2, 3. (2) Change in calculated Doppler blood flow versus change in supratentorial cerebral blood flow, calculated as the percentage of change from baseline measurements. Correlation coefficients and significance values for individual animals (LI-L12) are to the right of the chart. Bold line denotes the mean regression line for the entire group (slope of regression line, y = 1.17x - 6.56; r = .88, P = .0001). (3) Change in calculated Doppler blood flow versus change in supratentorial cerebral blood flow. Correlation coefficients and significance values for individual animals (L1-L12) are to the right of the chart. Bold line denotes the mean regression line for the entire group (slope of regression line, y = 0.13x + 6.54; r = .42, P = .001).
mated pixel size is 0.3 mm, and the resolution of caliper measurements is 0.1 mm (Hayes A, Acuson; oral communication; 1990).
Diameter Estimates Vessel walls could not be reliably detected with gray-scale US alone. We therefore attempted to use color Doppler information to estimate vessel diameter. Twenty to 30 seconds of flow were imaged in real time, stored in cine mode, and reviewed. Electronic calipers that display the mean frequency shift of a selected pixel were placed over the closest pixel at the edges of the vessel containing no flow information. The distance between these calipers was used to estimate the diameter of the vessel (Fig 1). Color Doppler imaging algorithms are proprietary information but are usually designed to depict the color hue proportional to the mean velocity of flow within the interrogated pixel. If a pixel is only partly overlying a vessel lumen, the entire pixel will be depicted as containing flow. The accuracy of these measurements was further limited by the relatively large pixel size determined with the lower frequency (5 MHz) used to create the color image. Thus, it is likely that the true internal diameter of the selected vessel is overestimated with this technique. Despite the presence of flow during diastole, as determined with spectral analysis, color information was often absent during diastole. Therefore, vessel diameters were obtained only during peak systole. Because of the twofold limitations of current color Doppler technology and small vessel size, we did not expect to obtain accurate measurements of absolute vessel diameter but rather were interested in evaluating color Doppler US as a tool to detect relative changes in vessel diameter with perturbations in CBF. At least 10 diameter mea-
Volume 176 * Number 1
surements were made at each sampling period and were averaged. The mean diameter was used for calculations of the volume of blood flow (hereafter referred to as volume flow).
Spectral Analysis and Blood Flow Determinations
A velocity spectrum containing at least 10 cardiac cycles was fixed on the display screen. An on-board spectrum analyzer was used to calculate the mean blood flow velocity averaged over time. This was accomplished by placing electronic calipers at each end of the spectrum and measuring the average of all the instantaneous mean velocities over this time interval (approximately 3.5 seconds). This procedure was repeated at least five times at each experimental interval. A 1.0 X 1.5-mm cylindrical sample volume was used, and the angle of insonation was held at 15°-45°. The computed velocity was based on the angle measured on the image. A 125-Hz high-pass filter (lowest setting) was used for all measurements. Volume flow (Doppler blood flow in milliliters per minute) was estimated with the formula (7rr2 60 sec * mean velocity). RI was calculated at each interval by means of the Pourcelot formula modified by Bada et al (15): ([systolic velocity - diastolic velocity] /systolic velocity). -
Experimental Protocols Three separate experimental conditions were used to vary CBF. Protocol A (five lambs) consisted of a 60-minute control period, followed by 120 minutes of hypocapnea and normoxia, 60 minutes of hypoxia and hypocapnea, 30 minutes of hypoxia and normocapnea, and 30 minutes of normoxia and normocapnea. In protocol B (five lambs), the order of the first two experimental conditions in protocol A
was reversed (ie, 60 minutes of hypoxia and normocapnea, followed by 120 minutes of hypoxia and hypocapnea, etc). In protocol C, two hypotensive animals were treated with a constant infusion of either phenylephrine or epinephrine for 30 minutes, followed by a measurement obtained 30 minutes after discontinuation of either drug. Although the individual effects of hypoxia or hypocapnea on CBF were difficult to discern with these protocols, we thought they approximated the clinical conditions most often experienced in infants with severe respiratory distress. Doppler measurements of blood flow velocity, RI, and vessel diameter were obtained simultaneously with injections of radiolabeled microspheres during each
experimental condition.
Data Analysis Doppler measurements of diameter, systolic velocity, diastolic velocity, mean blood flow velocity, RI, and Doppler blood flow were correlated with CBF determined by means of microsphere injection. Both absolute and relative changes in CBF (expressed as the percentage of change from baseline values) were used in these analyses. Correlations were tested by means of simple and multiple linear regression models. Differences in physiologic variables, such as arterial Po2, Pco2, and mean blood pressure during different experimental conditions, were analyzed by using a factorial analysis of variance (ANOVA).
RESULTS A summary of the protocols and mean arterial blood pressure, Pa2, and PCo2 values during each condition are listed in Tables 1-3.
Radiology * 233
Doppler Blood Flow versus CBF A wide range of CBF was produced with manipulation of arterial blood gases and blood pressure. CBF varied from 17.7 to 135.7 mL/min per 100 g of brain tissue (relative change in CBF, -70% to 136% from baseline values). Relative Doppler blood flow varied over a similar range (-67% to 157% change from baseline values) and correlated well with changes in CBF both within individual animals and for the entire group (Fig 2; y = 1.17x 6.56, r = .88, P = .0001). The relationship between relative Doppler blood flow and CBF was further corroborated by comparing changes in CBF to changes in mean blood flow velocity and diameter by means of multiple linear regression. This model assumes that the variables predict more information collectively than each could predict independently of the other. The change in both diameter and mean blood flow velocity contributed significantly to predicting change in CBF (regression coefficient = 0.61, P = .0001 for change in mean blood flow velocity; regression coefficient = 1.29, P = .0001 for change in vessel diameter; r = .87, P = .0001 for the entire model). Although absolute values for Doppler blood flow correlated well with absolute CBF in individual lambs, the correlation was weak between absolute values for Doppler blood flow and absolute CBF for the whole group (Fig 3; r = .42, P = .001).
3 50 Figure 4. Change > in mean blood flow 3 00 velocity versus change in supratenChn 2 torial cerebral blood Adog flow calculated as Bbod 200 the percentage of voloctty change from baseline measurements. Correlation coeffiI cients and signifi50 cance values for individual animals (LI-L12) are to the right of the chart. -so Bold line denotes the mean regres.10 0 sion line for the en0 25 50 .75 .50 .25 'hang. tire group (slope of In CBF regression line, y = 0.94x - 3.07; r = .79, P = .0001).
Vessel Diameter versus CBF
In general, mean vessel diameter tended to enlarge as CBF increased (Fig 8; r = .49, P = .0001). One exception to this observation was a hypotensive animal treated with intravenous phenylephrine, a potent vasoconstrictor. As CBF increased with infusion of phenylephrine, mean blood flow velocity and calculated Doppler blood flow increased concomitantly, while mean vessel diameter decreased by 19.5%. These pheFlow Velocity versus CBF nomena were not observed in the Changes in mean blood flow veloc- second hypotensive animal treated with epinephrine. No relationship ity alone also correlated well with was found between the change in obchanges in CBF (Fig 4; y = 0.94x served diameter and change in mean 3.07, r = .79, P = .0001), but the deblood flow velocity (r = .16, P > .2). gree of change in CBF tended to be Thus, it seems unlikely that an inunderestimated with these data. As shown in Figure 4, the slopes of most crease in estimated diameter was artiof the individual regression lines ficially caused by an increase in were below the line of identity. Abmean blood flow velocity detected at solute values for mean blood flow ve- or near the vessel edge. locity correlated poorly with CBF (r = .26, P 2 .2). Instantaneous peak DISCUSSION systolic and end-diastolic velocity Our data show that Doppler estimeasurements both showed only a of blood flow and mean blood mates r = weak correlation with CBF (Fig 5; correlate well with relflow velocity .46, P = .01, and r = .41, P = .02, reand that other frequently ative CBF spectively). used Doppler measurements, such as systolic and diastolic velocities and RI versus CBF RI, are only weak predictors of Increases in RI were principally change in CBF. due to a decrease in diastolic velocity, The measurement of mean blood with relatively little change occurflow velocity is relatively simple ring in systolic velocity (Fig 6). Alwith the use of color Doppler flow though RI correlated well with US for vessel localization, and the changes in cerebral perfusion presclose relationship between changes sure (r = .82, P = .0001), it correlated in mean blood flow velocity and only weakly with cerebrovascular re- changes in relative blood flow has sistance (Fig 7; r = .42, P = .02) and been demonstrated in several in vitro poorly with both absolute and rela(16,17), human (18,19), and animal tive values for CBF (r = .11, r = .17, (17,20) experiments. Our findings respectively; P > .2). There was no confirm this relationship and suggest that changes in mean blood flow vesignificant change in heart rate during each experimental interval. locity can probably be used to moni-
234 . Radiology
75 100 125 150 175
tor changes in relative CBF under most experimental circumstances. However, there are situations in which vessel diameter significantly changes (eg, during pharmacologic vasoconstriction), and the innacuracy of mean blood flow velocity measurements then increases. We confirm the prior findings by Sonesson and Herin (12) that suggested that changes in mean blood flow velocity tend to underestimate the true change in CBF. In the current study, the slope of the aggregate regression line comparing change in mean blood flow velocity and change in CBF is close to the line of identity (y = 0.94x - 3.07); however, most individual regression lines underestimate change in flow by approximately 50% (Fig 4). Measurements of peak systolic and end-diastolic velocities showed general trends that correlated with changes in CBF. However, the degree of variability was broad, and the value of these measures in predicting change in CBF was limited. Several authors have shown that accurate measurements of absolute flow are possible in vitro and in larger vessels (3.7-8.0-mm arteries) if the Doppler frequency shift and the diameter of the vessel are known (2123). Application of these techniques to the intracranial circulation has been difficult because of small vessel size and subsequent problems in determining vessel orientation and internal diameter when only gray-scale US is used. In this study, we used color flow imaging in an attempt to address these systematic limitations. Colorcoded flow information was helpful in obtaining accurate placement and sizing of the sample volume, as well as in determining the angle of the in-
July 1990
I 0.
70
*0
00
0 Dhm.0.
30
Voloo~y 0
0
40
20
0
S.
a. 0
20
I
ol.0
s 100 I50 200 % Chwop In CSF
50
0
210
350
300
400
-
500
050
I
100 100 200 % Chongo in CBF
200
200
250
400
b.
a.
Figure S. (a) Systolic velocity versus change in supratentorial blood flow (slope of regression line, y = 0.19x + 30.33; r = .59, p = .0004). (b) Diastolic velocity versus change in supratentorial blood flow (slope of regression line, y = 0.1x + 14.32; r = .48, p = .0063).
900
a00
0
70O FN 60a
0~~~~
0
ly unchanged, while diastolic velocities were lower with increasing RI values. However, equivalent changes in systolic and diastolic velocities can be present without affecting the RI (20,26). More important, many factors other than cerebrovascular resistance may affect the RI in an intracranial vessel. These include the presence of a patent ductus arteriosus and changes in heart rate and cardiac output, as well as the use of different high-pass filter settings while spectra are being obtained (27,28). Our data confirm that the RI is not a good predictor of changes in CBF and is only weakly related to cerebrovascular resistance. We conclude that relatively accurate estimates of change in intracranial blood flow are possible with duplex Doppler and color Doppler flow imaging and that studies in which instantaneous velocity measurements
00
~~O
40
0
SW
30 2 01 S00
40
0
70
00
0
1 00
00
1 10
1 20
1 30
14 0
Systoic Veotooty (on~feoc.)
Vaboooy foovomo)
Obsoolo
b.
a.
Figure
(a) RI
6.
peak systolic .55 velocity (r
blood flow
versus
diastolic blood flow
P
=
=
velocity (r
.05 P >
=
2).
RI
versus
end-
and the RI are used to assess changes in the cerebral circulation should be interpreted with caution. Further refinements in instrumentation and the development of small vessel flow phantoms may allow continued improvements in the accuracy of US flow measurements. U
.0001).
Acknowledgments:
We thank Deborah Flock,
Karen Bender, MD, and Maurizio Solca, MD,
cident beam to the direction of flow.
Although ume
absolute
of vol-
measures
flow correlated well with abso-
lute CBF in individual animals, abso-
probably resulted from several factors: changes in vessel diameter over time during the cardiac cycle, as well as an
overestimation of diameter due
to inclusion
of
may have contributed to inaccuracies
pixels containing color that were partly outside the vessel lumen; limited spatial resolution of color flow imaging at 5 MHz; and small vessel size. Yet, despite these
in blood flow determination with
limitations, estimates of vessel diam-
US. These include
eter
only pooled data
lute blood flow correlated
weakly with CBF when were analyzed. Several potential sources
of
error
for technical support.
References 1.
Volpe JJ.
the cross-sectional
ing
provided ing improved
in estimat-
area
of the
vessel, the angle of the incident beam, and the uniformity of insonation
across
Volpe Ji,
phy
were so
in the newborn: extensive
ple
volume size and could be
sam-
easily
rated
by
was
the presence of
a
corrobo-
is
unlikely
cation
the
or
angle
imaging,
it
inaccuracies in
of incidence
determining
signifiattempted
were
cant sources of error. We
changes use
of
The
Bashiru M, Russell J, Bada HS, Menke JA,
It is
to reduce errors in the determination
Doppler
of cross-sectional
minimizes the effect of
area
by repeating
the diameter measurements several times an
during
each interval and
using
average value for volume flow cal-
culations. Yet, estimation of the
cross-sectional
area
of the vessel
re-
likely source of ranthis study. Inaccuracies
mains the most
dom
error
in
in volume flow estimates with US
Volume 176 s Number 1Ra
5.
an
an
Volpe JJ.
Decrease in
hydrocephalus.
Bada HS, Miller
pulsatile
pulsatile
Pediatrics 1982;
JE, Menke JA,
et al.
In-
flow measurements in neonatal
intraventricular
probe place-
hemorrhage. J
Pediatr
1982; 100:291-296. 7.
Ahmann PA,
8.
Taylor GA, Short BL, Glass P, Ichord R. Cerebral hemodynamics in infants undergoing extracorporeal membrane oxygenation. Radiology 1988; 168:163-167.
indirect measurement of
velocity. Its utility is based on the assumption that changes in resistance affect diastolic flow velocity more than systolic velocity. In this study, systolic velocities remained relative-
in the prema-
tracranial pressure and cerebral arterial
measurement because it
The RI is
Hill A,
fantile
ment and can be
without
hemorrhage
infant. Pediatrics 1982; 69:144-149.
69:4-7.
attractive
easily obtained velocity signal calibration.
Volpe JJ. Relationpneumothorax to occurrence of in-
flow in the anterior cerebral artery in in-
indicator of cerebral
(5,11,25).
of
traventricular
6.
blood flow
Noninvasive detec-
Hill A, Perlman JM,
ship
multiple regression model. RI has been used by several as an
and hemor-
Bruit 1980; 4:619-623. 4.
a
authors
hemorrhage
intracerebral involvement. Pediat-
tion of neonatal cerebrovascular disease.
significant
and relative CBF with the
impair-
cerebral blood flow with
Miles R, Sumner D.
correlation between diameter
that nonuniform insonifi-
regional
JM,
tomogra-
rics 1983; 72:589-601.
3.
ture
identified with color flow
of
rhagic
velocity alone. The provided
with diameter estimates
study
small in relation to the
blood flow
mean
over
Positron emission
intraventricular
imag-
the accuracy of relative
volume flow measurements
Herscovitch P. Perlman
Raichle ME.
additional information
the vessel (24). Because
the vessels insonated in this
with color flow
inju-
153:243-251. 2.
ment
errors
Current concepts of brain
ry in the premature infant. AJR 1989;
Dykes FD, Lazzara A, et al. Relationship between pressure passivity and subependymal /intraventricular hemorrhage as assessed by pulsed Doppler ultrasound. Pediatrics 1983; 72:665-669.
Radiology,* 235
1
201
iol0
1 1
1 00
90
RI
% Change In
80
Vesx Diameter
0
70
-1
a 0 ..
5 0,
*
*@00 * 00
40
3 0 .1
.
.25
2.25 1 1.25 1 .5 1 .75 2 .75 Cerbrovascular ResIetance (mm Kglml/100 gm/ min)
.5
2.5
2.75
7. Figures
c
0
60
3
-75 -50 -25
25 50 0 % Chanp In CSF
75 100 125 150 175
8.
7,
(7) RI
versus
cerebrovascular resistance
(slope
of
regression line,
y
= -8.96x +
66.78;
r
=
.42, P
=
.02). (8) Change
in
mean ves-
sel diameter versus change in CBF, calculated as the percentage of change from baseline measurements. Correlation coefficients and significance values for individual animals (L1-L12) are to the right of the chart. Bold line denotes the mean regression line for the entire group (slope of regression line, y = 0.14x - 4.82; r .49, P = .0001). Arrow = individual regression line for hypotensive animal treated with intravenous phenylephrine. =
9. Mitchell DG, Merton D, Desai H, et al. Neonatal brain: color Doppler imaging. II. Altered flow patterns from extracorporeal membrane oxygenation. Radiology 1988; 167:307-310. 10. Seibert JJ, McCowan TC, Chadduck WM, et al. Duplex pulsed Doppler US versus intracranial pressure in the neonate: clinical and experimental studies. Radiology 1989; 171:155-159. 11. Horgan JG, Rumack CM, Hay T, MancoJohnson ML, Merenstein GB, Esola C. Absolute intracranial blood-flow velocities evaluated by duplex Doppler sonography in asymptomatic preterm and term neonates. AJR 1989; 152:1059-1064. 12. Sonesson SE, Herin P. Intracranial arterial blood flow velocity and brain blood flow during hypocarbia and hypercarbia in newborn lambs: a validation of rangegated Doppler ultrasound flow velocimetry. Pediatr Res 1988; 24:423-426. 13. Donegan JH, Traystman RJ, Koehler RC, Jones MD, Rogers MC. Cerebrovascular hypoxic and autoregulatory responses during reduced brain metabolism. Am J Physiol 1985; 18:421-429. 14. Heyman MA, Payne BD, Hoffman JIE, Rudolph AM. Blood flow measurements with radionuclide-labeled particles. Prog Cardiovasc Dis 1977; 20:55-77. 15. Bada HS, Miller JE, Menke JA, et al. Intracranial pressure and cerebral arterial
236 Radiology
16.
17.
18.
19.
20.
21.
pulsatile flow measurements in neonatal intraventricular hemorrhage. J Pediatr 1982; 100:291-296. Lundell BP, Lindstrom DP, Arnold TG. Neonatal cerebral blood flow velocity. I. An in vitro validation of the pulsed Doppler technique. Acta Pediatr Scand 1984; 73:810-815. Batton DG, Hellmann J, Hernandez MJ, Maisels MJ. Regional cerebral blood flow, cerebral blood velocity, and pulsatility index in newborn dogs. Pediatr Res 1983; 17:908-912. Rosenkrantz TS, Oh W. Cerebral blood flow velocity in infants with polycythemia and hyperviscosity: effects of partial exchange transfusion with Plasmanate. J Pediatr 1982; 101:94-98. Greisen G, Johansen K, Ellison PH, Fredriksen PS, Mali J, Friis-Hansen B. Cerebral blood flow in the newborn infant: comparison of Doppler ultrasound and 133-xenon clearance. J Pediatr 1984; 104:411-418. Hansen NB, Stonestreet BS, Rosenkrantz TS, Oh W. Validity of Doppler measurement of anterior cerebral artery blood flow velocity: correlation with brain blood flow in piglets. Pediatrics 1983; 72:526-531. Brody WR, Meindl JD. Theoretical analysis of the CW Doppler ultrasonic flowmeter. IEEE Trans Biomed Eng 1974; 21: 183-192.
22. Walter JP, McGahan JP, Lantz BMT. Absolute flow measurement using pulsed Doppler US. Radiology 1986; 159:545-548. 23. Loftus CM, Silvidi JA, Becker JA, Miller BV, Bernstein DD. Correlation of experimental rCBF determinations in goats with flow measurements from a Doppler-modified carotid artery shunt. J Ultrasound Med 1989; 8:7-13. 24. Gill RW. Measurement of blood flow by ultrasound: accuracy and sources of error. Ultrasound Med Biol 1985; 2:625-641. 25. Grant EG, White EM, Schellinger D, Choyke PL, Sarcone AL. Cranial duplex sonography of the infant. Radiology 1987; 163:177-185. 26. Rosenberg AA, Narayanan V, Jones MD. Comparison of anterior cerebral artery blood flow velocity an cerebral blood flow during hypoxia. Pediatr Res 1985; 19:6770.
27. Perlman JM, Hill A, Volpe JJ. The effect of patent ductus arteriosus on flow velocity in the anterior cerebral arteries: ductal steal in the premature infant. J Pediatr 1981; 99:767-771.
28. Taylor GA, Martin G, Short BL. Cardiac determinants of cerebral blood flow during ECMO. Invest Radiol 1989; 24:511516.
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