1. Original article
Clearance of thallium-201 from the peripheral blood:
comparison of immediate and standard thallium-201 reinjection
Berthe L.E van Eck-Smit 1, Ernst E. van der Wall 2, Patrick P.A.M. Verhoeven 1, Suzanne Poots 1, Aeilko H. Zwinderman 3,
Ernest K.J. Pauwels 1
1 Department of Diagnostic Radiology and Nuclear Medicine, Leiden University Hospital, Building 1 C4-Q77, Rijnsburgerweg 10,
2333 AA Leiden, The Netherlands
2 Department of Cardiology, Leiden University Hospital
3 Department of Medical Statistics, Leiden University Hospital
Received 7 August and in revised form 19 October 1995
Abstraet. As several reinjection procedures have shown that reinjection of 37 MBq (1 mCi) 2°1T1 (half the initial
encouraging results in terms of imaging, we investigated dose) results in a relative increase in the initial peak and
whether the kinetics of thallium-201 would differ be- a relative increase in the amount of 201T1 delivered to the
tween the standard stress-redistribution-reinjection ap- myocardium of more than 50% for both the standard and
proach and the stress-immediate reinjection approach. In the immediate reinjection procedure. The clearance of
53 consecutive patients with undiagnosed chest pain, 75 2°1T1 from the blood was not influenced by exercise or
MBq (2 mCi) 2°1T1 was injected at maximal exercise. In by the time of reinjection. Based on a01T1 kinetics as
26 of these patients (group I), 37 MBq (1 mCi) 2°1T1 was measured in the peripheral blood, there is no reason to
reinjected immediately after completing the exercise im- postpone reinjection until 3-4 h following exercise.
ages (the immediate reinjection procedure) and in 27 pa-
tients (group II), 37 MBq (1 mCi) 20lT1 was reinjected Key words: Thallium-201 scintigraphy - Thallium-201
after completing 3-h redistribution images (the standard kinetics - Thallium-201 reinjection
reinjection procedure). Mean peak 201T1 blood activity
after exercise was 17.7+12.5 kBq/ml (4.8_3.4 mCi/ml) Eur J Nucl Med (1996) 23:188-194
for group I versus 16.4_9.2kBq/ml (4.4___2.5 mCi/ml)
for group II (NS). The relative increase in 2roT1 blood
activity after reinjection of half the initial dose [37 MBq
(1 mCi)] exceeded 50% of the initial peak in both Introduction
groups. The relative amount of 2°1T1 delivered to the
myocardium was assessed by the area under the curve Since 1976 thallium-201 myocardial scintigraphy has
after both exercise and reinjection, and was 117%_+72% been extensively used in the clinical evaluation of pa-
for group I and 112%+73% for group II (NS). Blood tients with known or suspected coronary artery disease
clearance of amT1 was at least biexponential. Mean early [1-6]. This non-invasive technique provides information
decay constants (~1) after exercise and reinjection were on regional myocardial flow differences, flow changes
0.30_0.18 min -1 and 0.22_+0.046 min -1 respectively for under different conditions and viability of dysfunctional
group I (T 1/2 2.3 min and 3.2 min respectively, NS), and myocardium.
0.30_0.12 min -1 and 0.24___0.07 min -1 respectively for Because of the capability of 2OLT1to redistribute, Po-
group II (T m 2.3 min and 2.9 min respectively, NS). For host et al. [7, 8] proposed an imaging procedure in which
both procedures no significant differences were found exercise imaging was followed by 3- to 4-h delayed im-
between )~1 after exercise and )~1 after injection. The aging. Persisting defects after redistribution were con-
mean late clearance ()~2) from the blood was sidered to represent scar tissne, and reversible defects
0.032+0.056 min -~ and 0.012+0.012 min -1 respectively were considered to represent reversible ischaemia. This
for group I (Tl/2 21.6 min and 57.7 min respectively, concept has been challenged in recent years because
NS), and 0.036_+0.030 min -1 and 0.014+0.014 min -1 re- 45%-75% of myocardial segments with apparently fixed
spectively for group II (7"1/2 19.3 min and 49.5 min re- 2roT1 defects have been found to demonstrate increased
spectively, NS). Also, no significant differences were 201T1 uptake after revascularization [9, 10]. In a substan-
found between )~2 after exercise for both groups and be- tial number of these "falsely persistent" defects after re-
tween )~2 after reinjection for both groups. We conclude distribution, reversibility could be unmasked by repeated
imaging after 24 h or after reinjection of a second dose
Correspondence to: B.L.F. van Eck-Smit of 2°1T1 [11-13]. It has been assumed that a stress-in-
European Journal of Nuclear Medicine
Vol. 23, No. 2, February 1996 - © Springer-Verlag 1996

2. 189
duced defect may fail to show redistribution because of Table 1. Patient characteristics and exercise parameters (bpm
rapid decay of 2°1T1 blood activity [14]. In theory, rein- beats per minute; values within parentheses denote percentages
jecting a second dose of 2°1T1 after restoration of base- unless otherwise indicated)
line flow should promote redistribution of 2°iT1, and
Group I Group II P value*
therefore resolve exercise-induced perfusion defects.
Although left ventricular dysfunction may persist for No. of patients 26 27
a significant time (stunning) after stress-induced isch-
Age (years) 57+11 59_+10 NS
aemia [15], flow will return to baseline resting levels
(range) (28-72) (38-75)
within 30 min after maximal exercise regardless of the
severity of stenosis [16-18]. Moreover, left ventricular Males 20 (77) 22 (85) NS
dysfunction as a result of stunning does not affect myo- Previous myocardial 11 (42) 12 (44) NS
cardial 201T1extraction and washout kinetics [19]. Sever- infarction
al reinjection protocols have been proposed [12, 13, Maximal heart rate (bpm) 136+27 139_+30 NS
20-22]. Dilsizian et al. [12] and Rocco et al. [13] inject- (range) (89-194) (66-200)
ed an additional dose of 37 MBq (1 mCi) immediately Maximal systolic 189_+34 181 +25 NS
after delayed imaging and then performed repeated im- blood pressure (mmHg)
aging. Others have proposed reinjection of 75 MBq (range) (110-250) (110-240)
(2 mCi) 201T1 on a separate day [20]. Both protocols Double product/1000 26_+8 26-+7 NS
have the relative disadvantage of a prolonged investiga- (bpmxmmHg)
tion time. In previous studies from our. insdtution [21, (fange) (11-41) (7-38)
22], immediate reinjection of 2°1T1 after completing the
exericse images followed by imaging 60 min later yield- * P values of )~2 or Student's t-test
ed encouraging results in the identification of reversible
stress-induced perfusion defects within a time window
The imaging procedure was repeated 3 h after redistribution fol-
of only 2.5 h. Although the immediate reinjection proce- lowing exercise and 1 h after reinjection.
dure was shown to be of similar diagnostic value as the Baseline characteristics and exercise parameters were similar
standard reinjection procedure in terms of imaging [21], for both groups (Table 1).
the kinetics of 201T1 for both procedures have not been
well established. Based on the close relation between
2roT1 blood activity and 2°1T1 myocardial uptake, the aim Study protocol
of our study was to compare 2°1T1 kinetics between the
standard and the immediate reinjection procedure and to In all patients, peripheral venous blood was serially sampled (2 ml
per sample). Samples were drawn from the same intravenous line
investigate whether exercise or shortening of the interval
as was used to administer 201T1. After administration of 2°iT1, the
between exercise and reinjection would influence 2°1T1
system was flushed with 10 ml 0.9% NaC1. Before sampling, a 2-
kinetics in the peripheral blood. ml pre-sample of blood was drawn from the system. This wäy of
sampling was chosen for practical reasons: for least interference
with the clinical procedure and therefore an optimal chance of ad-
Materials and methods equate sampling. To justify this procedure we studied three pa-
tients by two separate intravenous lines who showed no differ-
ences in sample activities.
Patient selection For group I, a total of 19 venous blood samples were drawn: (l)
eight samples following exercise 201T1 injection, including the ex-
Our study consisted of 53 consecutive patients referred to the De- ercise imaging period, at 1, 3, 5, 7, 9, 12, 15 and 20 min, (2) one
partment of Nuclear Medicine for 2°1T1 scintigraphy for the evalu- sample just before 201T1 reinjection at 30 min, (3) eight samples at
ation of anginal complaints mostly associated with inconclusive 1, 3, 5, 7, 9, 12, 15 and 20 min following reinjection, and (4) orte
exercise electrocardiograms. The patients ranged in age from 28 sample at the beginning and one sample at the end of the reinjec-
to 75 years (mean age 58+11 years); there were 43 men and ten tion imaging period. For group II, apart from the above-mentioned
women. Twenty-three patients had sustained a previous myocar- sampling times, two additional blood samples were drawn, one
dial infarction. sample at the beginning and one sample at the end of redistribution
All 53 patients performed exercise in an upright position on a imaging, resulting in 21 samples per patient for group Il.
calibrated bicycle ergometer, as previously described [21]. Briefly, The study protocol was approved by the Institutional Review
at maximal exercise, 75 MBq (2 mCi) 201Tl was injected through Committee and all patients gave informed consent.
an indwelling intravenous cannula; exercise was continued for 1
min thereafter. Imaging was performed starting 5 min after termi-
nation of exercise. In 26 patients, 37 MBq (1 mCi) 2°1Tl was rein- Sample analysis
jected immediately after completing the exercise images accord-
ing to the immediate reinjection procedure (group I) [22]. Imaging Samples were counted for 4 min per sample in a Packard 7-spec-
was repeated 1 h after reinjection. In 27 patients, 37 MBq (1 mCi) trometer set with a 60- to 185-keV energy window. Counts per
201T1 was reinjected after completing 3-h redistribution images, sample were normalized to a standard sample (C1), containing a
according to the standard reinjection procedure (group II) [12]. known amount of activity. Measurements were corrected for sam-
European Journal of Nuclear Medicine Vol. 23, No. 2, February 1996

3. 190
ple weight (Ws-W0 and decay between time of sampling (ts) and ter 201Tl injection, were excluded from analysis because peak ac-
time of m e a s u r e m e n t (tm). A conversion factor of 1.03 g/tal (spe- tivity had not been reached in all patients.
cific gravity of blood) was used to convert the obtained values to
kBq/ml (btCi/ml). Blood activity [kBq/ml (gCi/ml)] at the time of
sampling was calculated using the following equation: Stat&tical analysis
CountS(s) xe -4 (t m --rs) xC' xl.03
The significance of differences between the mean values+_SD of
A(ts) (Ws - W t) , patient characteristics and exercise parameters for both groups
where A(ts)=201T1 blood activity at time of sämpling was tested using the )~e test or Student's t-test.
[kBq([xCi)/ml], Counts(s)=measured counts in sample, e -~-(t
m- Grouped data were expressed as the mean+SD. The signifi-
ts)=correcfion for decay between ts and tm, Cl=standard sample cance of a difference between (1) both groups or (2) post-exercise
[kBq(gCi)/count], 1.03=specific gravity of blood (g/tal), and post-reinjection was assessed using the paired or unpaired
W~=weight of sample (g), and Wt=weight of empty tube (g). Student's t-test. Very skewed distributed data were compared us-
ing the non-parametric Mann-Whitney or Wilcoxon's test whereas
the approximately normally distributed variables were compared
using the parametric Student's-t test. A P value <0.05 was consid-
Data analysis ered significant.
From the obtained data, time-activity curves were constructed for
each patient. From these curves, peak activity after exercise injec-
tion [A(te×)], residual activity before reinjection [A(tres)] and peak Results
activity after reinjection [A(trei~)] were defined. In every patient
the absolute increase in blood 201T1 activity after reinjection B l o o d 2°1Tl activity versus time
[T(abs)] was calculated using the following equation:
Figure 1 shows the mean blood 2°iT1 activity clearance
1(abs)=A(trein)-A(tres). curves over time after exercise injection and reinjection
for all 53 patients.
Because of the expected skewed distribution of the absolute 2°iT1 The mean p e a k 201Tl blood activity after exercise was
blood activity values due to the population inhomogeneity in 17.7+_12.5 kBq/ml (4.8+3.4 mCi/ml) for group I (imme-
terms of body weight and exercise level reached, we also deter-
diate reinjection) versus 1 6 . 4 + 9 . 2 k B q / m l (4.4_+2.5
mined the relative increase in 2roT1 blood activity after reinjection
[I(rd)], in all patients. The absolute increase in 2roT1 was related to mCi/ml) for group II (standard reinjection) (NS). The
peak activity after exercise using the following equation: mean residual 201T1 blood activity measured just before
reinjection was 0.88+0.48 kBq/ml (0.024+-0.013 mCi/ml)
/(rel) = ((abs). X100% for group I, and 0 . 7 2 _ 0 . 6 4 k B q / m l (0.019+-0.017
A(tex ) mCi/ml) for group II (NS). After reinjection, mean peak
The amount of 201T1 delivered to the myocardium was assessed 201T1 blood activity was 12.61+9.15 kBq/ml (0.34+-0.25
by the area under the time-activity curve after exercise and rein- mCi/ml) for group I, and 8.03+4.02 kBq/ml (0.22+_0.11
jection using Simpson's rule or the trapezoidal rule [23]. The ab- mCi/ml) for group II (P <0.05).
solute amount of ZmT1 delivered to the myocardium [Tl(abs)] was M e a n absolute increase in 2°1T1 blood activity after
defined as the area under the curve between the time of 2°lT1 ad- reinjection was 11.8+_9.8 k B q / m l (0.32_+0.27 mCi/ml) for
ministration and the end of imaging, for both exercise and rein-
group I, and 7.3_+4.2kBq/ml (0.20+-0.11 mCi/ml) for
jection. Tl(abs) after reinjection was corrected for the residual
amount of 2°1T1 delivered to the myocardium as a result of ad- group II (P <0.05). M e a n relative increase after reinjec-
ministration of ZmT1 after exercise between the time of reinjec- tion was 8 4 % + 7 6 % for group I, and 56%_+47% for group
tion and the end of reinJectlon lmaging. The relative amount of II (NS). The relative increase in 2°1T1 blood activity after
201Tl delivered to the myocardium after reinjection [Tl(rJ was reinjection of half the initial dose exceeded 50% in both
defined as the absolute amount of 201Tl after reinjection related to groups. The absolute ämount of 2°iT1 delivered to the
the absolute amount of 2°lT1 after exercise using the following m y o c a r d i u m after exercise [Tl(abs,ex)] was 89+44
equation: k B q / m l x m i n for group I and 82+45 k B q / m l x m i n for
group II (NS). After reinjection the amount of 2°1T1 de-
Tl(abs'rein) ;,<100%,
Tl(rel ) = Tl(abs,ex) livered to the m y o c a r d i u m [Tl(abs,rein)] was 83_+35
k B q / m l x m i n for group I and 88+77 k B q / m l x m i n for
where Tl(abs.ex)=area under the curve between exercise-injection
group II (NS).
and the end of exercise imaging (kBq/mlxmin), and Tl(abs«~in)=ar-
ea under the curve between reinjection and the end of imaging The relative increase in the amount of e°lT1 delivered
(kBq/mlxmin). to the m y o c a r d i u m Tl(rel) was 117%+_72% for group I,
Frorn each time-activity curve computer-assisted, linear esti- and 112%_+73% for group II (NS).
mations of decay constants 0~) and half-times (Tl/2) were obtained Table 2 s u m m a r i z e s the results of the a b o v e - m e n -
(1) for the period between 3 and 12 min after administration of the tioned parameters.
tracer ()vl), and (2) for the period starting at 15 min after adminis-
tration of the tracer ()@ until reinjection (i.e. 30 min for immedi-
ate reinjection, 270 min for standard reinjection) or until the end
of sampling. The results of the first sample, obtained at 1 min af-
European Journal of Nuclear Medicine Vol. 23, No. 2, February 1996

4. 191
18-
~6-'
-~-Immediate reinjection (group [)
[
14 -~-Standard reinjection (group Il)
12-
10-
m
.Q
8-
.&,
b--
6- Fig. 1. Mean blood 201Tl activity clearance
g
curves over time after exercise injection and
g 4 reinjection in 53 patients. At maximal exercise
E
~~ 75 MBq (2 mCi) 2°1T1was injected in all
patients. In 26 patients 37 MBq (1 mCi) 201Tl
was reinjected immediately after completing
exercise imaging (group I), and in 27 patients
0.--
50 1O0 150 200 250 300 350 400 37 MBq (1 mCi) 2°~T1was reinjected after 3-h
time (minutes) redistribution imaging (group II)
Table 2. Peak 201T1 activity after exercise, and activity increase after reinjection (group I immediate reinjection protocol, group H stan-
dard reinjection protocol, NS not significant, AUC area under the curve)
Group I Group II P value
Mean SD Mean SD
Peak after exercise: kBq/ml (gCi/ml) 17.68(4.8) 12.48(3.4) 16.38(4.4) 9.18(2.5) NS
Residual activity: kBq/ml (gCi/ml) 0.88(0.024) 0.48(0.013) 0.72(0.019) 0.64(0.017) NS
Peak after reinjection: kBq/ml (gCi/ml) 12.6l(0.34) 9.15(0.25) 8.03(0.22) 4.02(0.11) <0.05
Absolute increase: kBq/ml (~Ci/ml) 11.84(0.32) 9.83(0.27) 7.31(0.20) 4.23(0.11) <0.05
Relative increase (%) 84.15 75.82 55.89 46.82 NS
Absolute amount (AUC): kBq/ml (gCi/ml) 89 44 82 45 NS
Relative amount (AUC) (%) 117 72 112 73 NS
Table 3. Decay constants ()~) and half-
times (Tl/2) Exercise Reinjection
)~1 T1/2 )~2 T1/2 )~] Tm )~2 T1/2
Patient group (min-~) (min) (min -1) (min) (min-1) (min) (min-1) (min)
I: Mean 0.30 2.3 0.032 21.6 0.22 3.15 0.012 57.7
SD 0.18 0.86 0.056 13.7 0.046 0.54 0.012 28.8
II: Mean 0.30 2.3 0.036 19.3 0.24 2.86 0.014 49.5
SD 0.12 0.64 0.030 8.8 0.07 0.48 0.014 24.7
Correlation of I(re# and Tl(re# to exercise level Blood clearance of 201Tlafter exercise injection
and reinjection at rest
To correlate relative increase in 2roT1 blood activity and
exercise achieved, linear regression analysis was used. Table 3 lists the mean values_+SD for the decay constants
l(rel) and Tl(re1) (y) and double product (x) were both re- and half-times as calculated for group I and group II.
lated for all 53 patients, and showed no significant corre- Blood disappearance after 3 min post-injection was
lation (r=-0.15 a n d - 0 . 1 3 respectively). This correlation multiexponential both after exercise injection and rein-
was expressed by the equation y=-l.3x+102 for I(rel) ver- jection at rest.
sus double product, and y=-l.3x+94 for Tl(re]~ versus For both groups no significant differences were found
double product. between )~1 (early decay constant) after exercise and X 1
European Journal of Nuclear Medicine Vol. 23, No. 2, February 1996

5. 192
after reinjection. Similarly, with respect to the mean late Limitations
clearance from the blood ()~2), determined from 15 min
after exercise until reinjection and from reinjection until The large interindividual variability of measurements
the end of sampling, for both groups no significant dif- due to the sampling method used, i.e. discrete time-fixed
ferences were found between ~2 after exercise and ~2 af- samples in the clinical setting, may have hampered the
ter reinjection. accurate assessment of true peak 2°IT1 blood levels and
clearancë shortly after administration. In particular, most
of the clearance is likely to have occurred within the first
Discussion 3 min after 20~T1 injection. This problem might have
been slightly reduced if measurements after immediate
This study is, to our knowledge, the first to describe and standard reinjection had been made within the same
tracer kinetics of 2°1T1 in humans following exercise, patient (paired observations), but this would have been
and to establish the influence of tracer reinjection at dif- cumbersome from an ethical point of view in terms of
ferent time intervals following exercise. radiation dose.
2°1Tl blood levels and delivery of 2°lTl 2°1Tl blood clearance
to the myocardium
Blood clearance of 2°1Tl after intravenous injection was
The results of the present study, performed in 53 consec- multiexponential and uninfluenced by exercise or by the
utive patients in a routine clinical setting, show that 201T1 time interval between injection and reinjection. The
blood levels and the amount of 2°1T1 delivered to the mean initial clearance half-times determined between 3
myocardium following reinjection of half the initial dose and 12 min after exercise and reinjection were 2.3_+0.86
increased by more than the expected 50% for both im- min and 3.2_+0.54 min respectively for the immediate re-
mediate and standard reinjection. The increase in blood injection procedure (group I), and 2.3+0.64 min and
level may be explained by a different biodistribution of 2.9_+0.48 min respectively for the standard reinjection
2roT1 during exercise compared to the resting stare be- procedure (group II).
cause of a more complete extraction by the myocardium The mean late clearance half-times determined from
and the peripheral muscles during the first minute fol- 15 to 30 min after exercise injection and from 15 min af-
lowing injection in the exercise state. Of course, this re- ter reinjection until the end of sampling were 21.6+13.7
mains speculative as we have no pharmacokinetic data min and 57.7+28.8 min respectively for group I, and
from the skeletal mnscles and visceral organs under dif- 19.3+8.8 min and 49.5-+24.7 min respectively for group Il.
ferent physiological conditions. The high amount of Differences between both reinjection procedures and be-
a01T1 delivered to the myocardium after reinjection was tween exercise and reinjection were not significant. Two
not only influenced by the blood level, but also by the separate reports on 2°1T1 kinetics by Okada etal. [25, 26]
longer period between administration of 2°lT1 and the confirm our observations of blood 2roT1 clearance being
end of imaging, which was 30 min for the exercise study uninfluenced by exercise. In these studies, performed in
versus 90 min for the reinjection study. anaesthetized dogs, Okada et al. reported a tliexponential
Although the mean absolute peak activity and the blood clearance for 2°1T1 after intravenous injection fol-
mean absolute increase after immediate reinjection lowing exercise and at rest. The initial-phase half-times
(group I) were significantly higher than after standard after exercise and rest were 1.9-+1.2 min and 2.4+1.1 min
reinjection (group II), this difference was abolished respectively; the middle-phase half-times, established by
when correction was made for the interindividual vari- 8.9-+0.5 min, were 11.4+7.7 and 14.1-+7.1 min respective-
ability in 2°1T1 blood levels (85%+76% for group I ver- ly; and the late-phase half-times, established by 44.6__4.7
sus 56%+47% for group II, NS) or when results were min, were 408-+277 and 445.4-+201.6 min, respectively.
expressed as the relative amount of 2°lT1 delivered to the
myocardium (117%-+72% for group I and 112%_+73%
for group II, NS). The relative increase after reinjection Limit~ions
[I(~~l)] and the relative amount of 2°1T1 delivered to the
myocardium [Tl(re1~] were unrelated to the exercise level Apart from the similarities between out findings and the
achieved. As flow returns to baseline values within min- data reported by Okada et al. [25, 26], absolute figures
utes after termination of exercise [24], shortening the in- and standards of the error differed substantially. On the
terval between exercise and reinjection may be at least orte hand, this may be explained by the evaluation of
equally as effective as the standard reinjection procedure 201Tl kinetics in the canine model under strictly con-
in delivering adequate amounts of tracer to ischaemic trolled conditions in their study, whereas out study was
myocardial regions. performed in humans under routine clinical conditions.
On the other hand, in the study performed by Okada et
al. [25, 26], sampling was continued for 240 min after
European Journal of Nuclear Medicine Vol. 23, No. 2, February 1996

6. 193
administration of 2°iT1. It was inherent to the procedure 5. Jambroes G, van Rijk PR ran de Berg CJM, de Graaf CN,
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