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Intraarticular volume and clearance in human synovial effusions.

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INTRAARTICULAR VOLUME AND CLEARANCE IN
HUMAN SYNOVIAL EFFUSIONS
WAYNE J. WALLIS, PETER A. SIMKIN, WIL B. NELP, and DAVID M. FOSTER
Intraarticular volumes were measured by radiolabeled albumin (RISA) distribution in chronic knee
effusions from 11 rheumatoid arthritis patients and 9
osteoarthritis patients. Volumes of synovial fluid obtained at joint aspiration were substantially less than
those found by RISA dilution. Up to 24 hours was
needed for full distribution of RISA throughout the
intraarticular compartment. Measured lz3I and RISA
radioactivity over the knee described monoexponential
rate constants, X (minute-'). The clearance of lz3I and
RISA from synovial effusions was derived by the formulation volume (mI) x x (minute-') = clearance
(ml/minute). RISA clearance in rheumatoid effusions
was significantly greater than that found in osteoarthritis effusions. Intraarticular volume and isotope clearance were easily quantified and provide measures for
further evaluating the microvascular physiology of synovial effusions.
Radiolabeled compounds exit synovial effusions at rates which can be used to quantify the
microvascular physiology of synovitis. Studies conducted with small solutes (2'Na, 13'1, and "'Xe) and
From the Departments of Medicine, Radiology, and Bioengineering, University of Washington, Seattle.
Supported in part by NIH grants AM-22186, AM-32811,
T32-AM-07108, and RR-37, and by a grant from the Western
Washington Chapter of the Arthritis Foundation.
Wayne J . Wallis, MD: Acting Instructor in Medicine; Peter
A. Simkin, MD: Professor of Medicine; Wil B. Nelp, MD: Professor
of Medicine and Rheumatology and Director, Division of Nuclear
Medicine; David M. Foster, PhD: Research Associate Professor of
Bioengineering.
Address reprint requests to Peter A. Simkin, MD, School of
Medicine, Department of Medicine, Division of Rheumatology,
RG-28, University of Washington, Seattle, WA 98195.
Submitted for publication May 21, 1984; accepted in revised
form October 23, 1984.
Arthritis and Rheumatism, Vol. 28, No. 4 (April 1985)
radiolabeled proteins (albumin and immunoglobulins)
have all revealed the monoexponential decline in radioactivity characteristic of first-order kinetics (1-6).
These constant rates mean that the departure of each
solute from the joint cavity can be expressed as a
single half-life (minutes) or, alternatively, a removal
rate constant (minutes-') (7).
One cannot fully interpret such rate constants,
however, without knowing the distribution volume of
the isotope. For example, a value of 0.05 minutes-'
would correspond to an articular clearance rate of 0.5
mlhinute from a small intraarticular volume of 10 ml,
but would reflect the much higher clearance of 5
mlhinute from a swollen volume of 100 ml. Such
compartmental clearances are calculated easily from
the product of compartmental volume, V (ml), and the
rate constant of solute removal, A (minute-'), a\
follows:
V (ml) X A (minute
') =
clearance (mlhinute)
Identical synovial clearances could result from a large
effusion with a slow removal rate or from a small
effusion with a rapid removal rate. These simple
examples emphasize the importance of volume considerations in evaluating isotope clearance from synovial
effusions.
In this report we describe a method of determining intraarticular volume and synovial clearances.
We hypothesized that articular solute clearances
would reflect the microvascular physiology of synovitis more accurately than rate constants of isotope
removal. We determined the removal rate constants of
'3'I-labeled albumin (RISA) and free j2'1 from the
synovial effusions of individuals with rheumatoid arthritis (RA) and osteoarthritis (OA). In the same
effusions we also derived, by isotope dilution, the
WALLIS ET AL
442
apparent distribution volume of RISA within the articular cavity and synovial tissues. These values have
enabled us to calculate the albumin and iodine clearances from synovial effusions.
PATIENTS AND METHODS
Patient selection. Individuals with clinically evident
knee effusions and rheumatoid arthritis or osteoarthritis
were referred by physicians at the rheumatology clinics of
the Affiliated Hospitals of the University of Washington.
Fully informed consent was granted by all study participants
through a protocol approved by the University Human
Subjects Committee. Patients were admitted to the Clinical
Research Center of University Hospital, where a history was
taken and physical examination performed prior to each
study.
Rheumatoid arthritis patients. Eleven individuals
with classic or definite rheumatoid arthritis (8) and chronic
stable knee effusions were included in this investigation. The
age, sex, duration of disease, and patient’s estimate of both
the duration of the effusion and duration of recent morning
stiffness are reported in Table 1. Six of 8 patients who had
undergone previous joint aspiration for knee effusion had
also received intraarticular corticosteroids an average of 7.5
months prior to study. Each patient’s medication regimen
was continued during the period of study in order to sustain
the steady-state effect of outpatient therapy. Eight patients
were receiving gold or penicillamine, 4 took oral prednisone
5 1 5 mg per day, and all were receiving aspirin and/or other
nonsteroidal antiinflammatory drugs.
Physical examination findings, including height,
weight, girth of the knee at mid-patella, range of motion, and
the presence of laxity and crepitation, are shown in Table 1.
Synovial (Baker’s) cysts were detected by physical examina-
Table 1. Clinical features of rheumatoid arthritis (RA) and osteoarthritis (OA) patients with synovial effusions
Patient
Age/
sex
Duration
Disease
of
duration, effusion,
years
months
Previous
joint
aspiration/
injection
(months
Morning
before
Height, Weight,
stiffness,
minutes
study)
Medications*
cm
kg
Knee
girth,
cm
Range of
motion,
Laxity/
degrees crepitance Cyst
RA
I
64IF
5
15
90
2
62lM
18
12
240
3
4
67lF
66lF
11
45
24
156
0
120
5
6
41/M
64lF
5
15
6
36
120
30
7
8
9
60lM
39lF
21/M
18
19
1.4
60
72
18
I20
10
60lF
60/M
10
20
72
42
11
Mean f SE 55 & 4
OA
1
41lF
2
75lM
3
4
5
6
7
8
9
Mean
74lF
54lM
45lM
57lM
86lF
60lM
27/F
f SE 58 t 6
15
?
4
0.4
3
5
3
8
20
3
16
6
722
15
360
0
0
NSAID, gold,
ASA
ti+ (3) DP, ASA,
Pred (10
mglday)
-/ASA
+I+ (4) NSAID. Pred
(3 mgiday)
NSAID
-1+I+ (6) NSAID, DP,
ASA
+I+ (6) Gold, ASA
Gold, ASA
+IGold, ASA,
+/Pred (15
rnglday)
DP, ASA
-I+/+ (24) NSAID, gold,
Pred ( 5 mgl
day)
+I+ (2)
47 t 13 100 ? 34t
2
36
10
15
36
36
6
19
72
120
I
37 t 13
20
20
20
0
0
0
10
I I t 3t
160
46.8
38
120
-li
178
91.8
43
75
-1-
168
163
55.9
56.8
41
39
135
125
+/+
168
155
58.6
46.4
38
36
90
120
-1+I+
170
170
193
60.0
53.2
85.9
35
37
45
100
135
-1-1-1-
152
188
76.8
95.5
39
44
135
135
+I+
-1-
170
-I-I-I-/il+It (2)
-I-I-1-
None
NSAID, Pred
(12.5 mgl
day)
NSAID
NSAID
ASA
NSAID
NSAID
None
NSAID
?
183
160
4 67
?
5 40
110.9
67.3
2 1
51
37
39
63.2
46
104.5
44
100.0
39
74.5
41
150
69.1
173
84.1
41
39
168
65.9
170 ? 4 82 2 6 42 2 1
163
173
183
180
110
ti+
1162 6
135
135
-1-I+
135
135
135
135
100
130
95
126k 5
-I+
-It
-1-
tl+I+
+I+/+
* NSAID = nonsteroidal antiinflammatory drug; ASA = aspirin; DP = D-penicillamine; Pred = prednisone.
t P < 0.05, RA patients versus OA patients. Differences between RA and OA groups were not significant for any other parameters.
VOLUME AND CLEARANCE IN EFFUSIONS
tion (RA patients 3, 4, 7, 8, and l l ) , scintigraphic imaging
(RA patients 3 and 7), or previous arthrography (RA patients
6 and 7). Serum rheumatoid factor by latex agglutination was
positive at a titer 2 1 :640 within the year prior to study in all
but 1 individual (RA patient 9). The mean serum hemoglobin
level was 13 gmidl.
Osteoarthritis patients. Nine individuals with chronic
osteoarthritis and stable knee effusions are also characterized in Table 1. Many of these patients had suffered significant trauma to the knee. Although the values were not
statistically different than those of RA patients, the OA
group had joint disease of shorter duration ( P = 0.08),
weighed more ( P = 0.07), and had knees of greater girth (P=
0.21) and wider range of motion ( P = 0.25). OA patient 2 was
receiving prednisone therapy for idiopathic thrombocytopenic purpura during the study. OA patient 6 was undergoing regular outpatient peritoneal dialysis for end-stage renal
disease and had a massive effusion and synovial cyst. OA
patient 7 had mild incidental hypothyroidism detected during
the study of her effusion, when synovial fluid (SF) was found
to string more than 3 feet from the aspirating syringe (9). The
diagnosis of hypothyroidism was confirmed by thyroid function tests. OA patient 8 had a synovial (Baker's) cyst
detected by physical examination.
Radionuclide pre aration. The sodium salt of iodine123 dissolved in water (pz31; half-life 13.3 hours) (Mediphysics, Emeryville, CA) was sterilized by passage through a
0.22-pm filter and tested by the limulus assay for absence of
endotoxin. 1311-labeledhuman serum albumin (13'1; half-life
193.9 hours; RISA concentration 10 mg/ml in H20, pH 7.6,
with 9 mg/ml benzyl alcohol as preservative) was purchased
from E. R. Squibb Co., New Brunswick, NJ. The nuclide
solutions (30 pCi of each) were combined, and the total
volume brought to 3 ml by the addition of isotonic saline.
One milliliter was stored as a quantitative standard and the
remaining 2 ml, containing 20 pCi of 1231and 20 pCi of
RISA, was used for intraarticular injection. The specific
activity of injectate (pCi 13'I/mgalbumin) varied with the age
of the RISA preparation in different studies.
Study protocol. Investigations were all initiated in the
morning, with patients fasting prior to study to assure a
stable blood glucose level. Patients drank 0.3 ml of Lugol's
solution 1 hour prior to study and each day during the
ensuing 2 weeks. in order to block thyroidal uptake of
radioiodine. Samples of venous blood were obtained through
an antecubital in-dwelling heparin-flushed cannula, with the
patient reclining on an examining table.
The knee was positioned at 30" of flexion and the
medial suprapatellar aspect superficially anesthetized with
2% lidocaine. An 18-gauge intravenous catheter was then
passed into the joint space until synovial fluid returned
freely, and a 5-ml aliquot was withdrawn for study. The 2-ml
double radionuclide solution was then injected into the knee,
followed by barbitage to promote intraarticular mixing and
then injection of 3 ml saline. The latter was employed to
flush all injectate from the dead space of the catheter and to
sustain the steady-state volume and hydrostatic pressure of
the initial synovial effusion. The catheter was promptly
withdrawn and intraarticular mixing and distribution of the
injectate was again promoted by massage as well as passive
flexion and extension of the knee for 5 minutes.
Radioactivity in the joint space and its rate of disap-
443
pearance were measured with a sodium iodide crystal (thyroid probe) 28 cm over the patella. At this distance the
collimator subtended a flat field response 18 cm in diameter
at the surface of the patella, and the relative counting
efficiency of 16% varied 0.8% per vertical cm. Thus, small
differences with repositioning of the knee created little
change in relative count rate. The counting of the 2 isotopes
was done using gamma spectrometry and dual channel
analysis. The photo peak was centered at 364 keV, with a
window equal to the full width at half maximum of the photo
peak. The lZ3Iactivity was similarly counted, with the photo
peak centered at 150 keV. The compton scatter of the I3'I
into the 1231photo peak was subtracted. This scatter fraction
averaged 19% and was determined by counting a fixed 13'1
source in 1 ml of water 28 cm from the crystal surface.
Counts were obtained at 5-minute intervals over the
first 3 hours and then every 2-4 hours until midnight.
Further counting resumed the following morning for total
periods ranging from 24-96 hours. In selected individuals,
serial joint imaging was accomplished with a Picker 4/11
gamma camera (Picker Corp., New Haven, CT) and a
computer (MDS Simul; Media Data Systems, Ann Arbor,
MI) calibrated for both isotopes. Between counting intervals, study patients were encouraged to ambulate at their
normal level of activity.
Aliquots of synovial fluid (0.2 ml) were obtained at 1
and 24 hours by repeat arthrocentesis with a 22-gauge needle
and tuberculin syringe. From 1 consenting individual with
seronegative rheumatoid arthritis (RA patient 9), additional
aliquots of synovial fluid (0.2 ml) were obtained every 24
hours over 3 days from bilateral, clinically identical knee
effusions. From 4 OA patients and 4 RA patients, additional
synovial fluid samples were taken at 24, 48, and 72 hours
after injection. At the end of each study, the entire synovial
fluid volume (V,) of the effusion was aspirated as thoroughly
as possible. 1231and I3'I radioactivities of the synovial fluid
samples (0.1 ml) and the quantitative standard (0.1 ml) were
measured in a Packard well-type scintillation detector using
dual channel analysis. For external surface counting and
well counting, counting statistics had a relative error of
55%.
Characterization of synovial fluid RISA activity. Studies were conducted to determine if intraarticular RISA
became aggregated or deiodinated within the joint space. I3'I
activity in 1 synovial, fluid sample obtained from RA patient
6, 24 hours after RISA injection was analyzed by sucrose
density gradient ultracentrifugation. Hyaluronidase (0.1 mg,
type I-S; Sigma, St. Louis, MO) was added to 2 ml of
synovial fluid and incubated at 37°C for 60 minutes. Hyaluronidase-treated synovial fluid (0.4 ml) diluted 1 : 1 (volumeholume) with phosphate buffered saline (PBS) and 0.4
ml RISA reagent diluted 1 :9 ( v h ) in PBS were characterized
on 5-30% sucrose gradients in borate buffered saline, and
run at 37,000 revolutions per minute at 4°C for 16 hours in a
SW41Ti rotor and Beckman L2-65 13 ultracentrifuge (Beckman Instruments, Spinco Division, Paln Alto, CAI.
Serial samples were collected and analyzed for radioactivity on an automatic gamma counter (Searle Radiographics, Des Plaines, IL). RISA activity in the injection
solution and in synovial fluid (24-hour aspirate) remained
monomeric without significant aggregation. In addition, I3'I
activities in the RISA reagent and in 2 synovial fluid samples
444
WALLIS ET A L
Statistical analysis included linear regression and
Student's I-tailed t-test, using the SPSS (1 1) and BMDP (12)
programs on a CDC-3000 computer.
RESULTS
0
0
0
0
0
O
0
0
0
0
a
0
0
0
0
0
04
0
0
20
40
1
60
80
100
120
Intraarticular volume in OA and RA synovial effusions. Preliminary studies revealed that RISA distribution volumes obtained by sampling synovial fluid 1 hour
after injection were significantly smaller than those
obtained at 24 hours. After 1 hour, the RISA distribution volume in all 9 OA effusions was 74 +- 33 ml (mean
? SEM), and after 24 hours, it was 109 5 35 ml. In the
1 1 RA effusions the 1-hour RISA distribution volume,
140
Distribution volume of albumin (ml)
Figure 1. Intraarticular volumes. Volume of synovial fluid obtained
at the termination of each study (V,) markedly underestimated the
apparent intraarticular distribution volume of '"I-labeled human
serum albumin (VRZ4).VA closely correlated with VRZ4in effusions
from osteoarthritis patients ( 0 )(r = 0.98). Aspirated volumes in
effusions from rheumatoid arthritis patients (0)were less predictive
of distribution volumes. One patient with a massive effusion and a
synovial cyst (osteoarthritis patient 6) is not included in this figure.
taken 24 hours after injection were studied by trichloroacetic
acid (TCA) precipitation. In all 3 samples, the TCA-precipitable I3'I activity was >99%.
Clearance kinetics. External radioactivities over the
knee for 1231and "'I were graphed and the removal rate
constants for each isotope (corrected for physical decay)
were obtained by regression analysis on a VAXII/780 computer using the SAAM 27 computer program (10). The R2 of
the "best fit" regressions of declining RISA radioactivity
was 0.94 5 0.03 (mean t SE) in RA and 0.98 t 0.01 in OA.
Similarly, the R2 of the 1231regressions was 0.93 & 0.02 in
RA and 0.92 +- 0.03 in OA. In all cases, 1231 and I3'I
radioactivities declined monoexponentially. Disappearance
half-lives were calculated from the removal rate constants
using the expression, half-life (t1,2) = 0.693ih.
Apparent distribution volumes for intraarticular
RISA ( V R ~were
~ ) calculated from the equation
Vu24
=
An
X
8
0
0
-
8
0
0
0
0
0
0
0
0
VJA24
where An and Vo represent the activity (counts per minrepresents
utelml) and volume (ml) of the injectate, and
the activity of the SF aspirate obtained at 24 hours, corrected for isotope cleared from the joint (aspirated activity
extrapolated back to time zero).
was obtained by multiplying the 24-hour aliquot (cpm/ml) by the externally monitored radioactivity at time zero (cpm) (No) and dividing by
RISA NZ4(both N taken from the computer-derived regression line of external RISA activity). Clearance of RISA from
synovial effusions (mllminute) was derived from the product
of VRZ4(ml) and RISA (minutes-'). Iodine clearance was
calculated from the product of VRZ4and A'231.
cyst
Positive
cyst
Negative
Figure 2. Popliteal cysts and intraarticular volumes. The presence
of a popliteal cyst (detected by physical examination, previous
arthrography, or scintigraphic imaging) did not significantly change
the apparent distribution volume of intraarticular 1311-labeledhuman
serum albumin. Most cysts were found in individuals with rheumatoid arthritis (0).Osteoarthritis patient 6 is not included in the
osteoarthritis data ( 0 ) .
445
VOLUME AND CLEARANCE IN EFFUSIONS
/B
.....
-I
lo5
..._..
'. ..0 . . .SF, plsA
...__.
....
I
0
IOZ!
0
!
Ib
I
20
1
30
1
40
Hours
I
I
I
50
60
70
Figure 3. Kinetics of isotope removal. Semilogarithmic plot of
activity over time for 12?1 and 1311-labeledhuman serum albumin
(RISA) after injection into the stable knee effusion of an individual
with osteoarthritis (OA patient 4). Externally monitored radioactivity of RISA (A) and '231 (0)describes monoexponential plots with
RISA intraarticular half-life approximately 36 times that of '''I.
Synovial fluid (SF) RISA activity (0)
(counts per minuteiml) declined rapidly (distribution phase) and subsequently paralleled externally monitored RISA at 24 hours. Plots are corrected for
Compton scatter and isotope physical decay.
45 2 10 ml, was significantly less than the V R 2 4 , 105 t
7 ml. RISA distribution volumes were also derived
from synovial fluid samples taken at 48, 72, and 96
hours in 4 patients with OA and 4 with RA. The
derived distribution volumes at these later times did
not significantly differ from those obtained at 24 hours.
The volume of synovial fluid aspirated from OA
effusions was consistently less than that determined by
RISA distribution, but a close correlation was observed between aspirated volume and VRZ4( P = 0.001,
r = 0.98) (Figure 1). Osteoarthritis VA averaged 28 +
60, or -19% (geometric mean + 1 SD) of VRZ4.
Aspirated volume from RA effusions correlated less
consistently with RISA distribution volume (P =
0.091, r = 0.43), primarily because VA markedly
underestimated VR24 in 2 individuals (RA patients 7
and 8). The geometric mean VA in rheumatoid arthritis
was 27 + 22 or -12% of VR24. The presence of a
synovial cyst (as defined in Patients and Methods) did
not significantly affect VR24 (Figure 2).
Kinetics and clearance of radionuclide removal
from synovial effusions. In accordance with previous
findings (7), radioactivity over the knee from each
isotope (free 1231and albumin-bound 13'1) declined
Table 2. Intraarticular volumes and isotope clearance determinations in rheumatoid arthritis (RA) and osteoarthritis (OA) patients with
synovial effusions*
(mli
Patient
V A (ml)
(ml)
RISA ti12
(minutes)
RISA (R')
Iodine tli2
(minutes)
12?1 (R')
minutes)
C, (mli
minutes)
1
2
3
4
5
6
7
8
9
10
II
Mean 2 SE
OA
I
2
3
4
5
6
7
8
9
Mean 2 SE
44
39
34
33
20
44
12
9
65
22
33 t 5
I37
I20
94
79
76
95
74
124
134
121
I06
105 2 7
1,540
877
1,050
877
1,260
1,506
976
613
1,174
1,358
900
1,102 2 83t
0.98
0.99
0.95
0.91
0.92
0.66
0.99
0.99
0.99
0.98
0.99
0.94 t 0.03
69
35
53
69
41
69
53
29
29
29
24
45 2 5
0.91
0.94
0.98
0.88
0.92
0.92
0.81
0.97
0.99
0.98
0.90
0.93 2 0.02
0.062
0.095
0.062
0.062
0.042
0.044
0.053
0.140
0.079
0.062
0.082
0.071 ? 0.028$
1.37
2.40
1.22
0.79
1.29
0.95
0.96
2.98
3.22
2.90
3.07
1.92 t 0.30
59
20
1
12
54
267
16
94
7
59 2 28
97
74
53
43
86
379
59
I28
60
109 C _ 35
2,772
1,733
2,235
1,414
1,690
2,310
1,611
1,650
1,414
1,870 k l55t
0.96
0.99
0.98
0.91
0.99
0.99
0.98
0.99
0.99
0.98 2 0.01
41
41
33
58
23
46
46
41
12
38 2 5
0.92
0.98
0.90
0.99
0.99
0.73
0.98
0.85
0.97
0.92 ? 0.03
0.024
0.030
0.016
0.021
0.035
0.114
0.025
0.054
0.029
0.039 2 0.030-i
1.65
1.26
I .59
0.52
2.58
5.69
0.89
2.18
3.36
2.19 i 0.52
VRZ4
CRlSA
RA
41
* VA = volume of synovial fluid by joint aspiration (at end of study); VR24= apparent intraarticular distribution volume of '311-labeledhuman
serum albumin (RISA) 24 hours after injection; ti/* = half-life of isotope marker in the knee as measured by external gamma emission counting;
= clearance of albumin; CI = clearance of iodine. See text for clearance calculation methods.
t P < 0.005, RA patients versus OA patients.
$ P < 0.05, RA patients versus OA patients.
WALLIS ET AL
446
0
l o o
Figure 4. Articular scans. Lateral knee scintigraphic imaging of the
intraarticular IZ3I and '311-labeled human serum albumin (RISA)
indicates that RISA activity declines more slowly with time than
'"1. These images (from osteoarthritis patient 8) suggest that both
isotopes are largely confined to the intracapsular compartment. IZ3I
activity imaged at 24 hours represents Compton scatter from RISA
into the IZ31energy window.
over time in monoexponential fashion (see example in
Figure 3). The average elimination half-life for RISA
was 1,102 ? 83 (mean r SE) minutes in RA effusions
and 1,870 k 155 minutes in OA effusions. The correwas 45 5 5 minutes in
sponding mean half-life for 1231
RA effusions and 38 k 5 minutes in OA effusions.
Table 2 illustrates the marked differences in rate
constants of isotope removal, both between individuals and between diagnostic groups. In addition, the
distribution image of both radionuclides did not expand beyond the immediate articular region with serial
joint scans (Figure 4). As in any study utilizing radiolabeled proteins in vivo, we necessarily assumed that
the administered radioalbumin was not deiodinated
within the joint.
Intraarticular volume, defined by apparent distribution volume of injected RISA, was multiplied by
the removal rate constants obtained for RISA and Iz3I
to derive the synovial clearances in ml/minute. The
product of V R 2 4 (ml) and X'231 (minutes-') is the
synovial iodine clearance (ml/minute). The product of
V R 2 4 (ml) and RISA yields RISA clearance (ml/minute). The mean iodine clearance in RA effusions (1.92
-t 0.30 ml/minute) was comparable with that found in
OA effusions (2.19 0.52 ml/minute) (Table 2). Figure
*
8
I
a
L : 0
RA OA
RA OA
Figure 5. Synovial clearances of iodine and radioalbumin. Scattergrams of calculated IZ3I clearance and "'I-labeled human serum
albumin clearance from the synovial effusions of individuals with
osteoarthritis (OA) and rheumatoid arthritis (RA). Synovial Iz31
clearances were comparable from RA and OA knee joints (P =
0.663), while synovial protein clearance was significantly higher in
RA than in OA joints (P = 0.024).
5 emphasizes the wide distribution of synovial iodine
clearance values found in our sample of rheumatoid
synovial effusions. The mean RISA clearance in RA
patients (0.071 ? 0.028 ml/minute) was significantly
greater than that found in OA patients (0.039 ? 0.030
ml/minute). Protein clearance was greater in every RA
effusion than in every OA effusion except that from
OA patient 6, who had a massive effusion and a RISA
distribution volume of 379 ml.
Recirculation of RISA from plasma to synovial
fluid. In order to assess the possible contribution of
recirculated RISA, we measured radioactivity in serial
samples of synovial fluid from both the injected knee
VOLUME AND CLEARANCE IN EFFUSIONS
Hours
Figure 6 . Radioalbumin recirculation. Semilogarithmic plot of I3'Ilabeled human serum albumin (RISA) activity (counts per minute/ml) in serial samples obtained from synovial fluid of the injected
and synovial fluid (A)from a clinically
knee ( O ) , and serum (0)
similar contralateral knee effusion from an individual with seronegative rheumatoid arthritis. Assuming that the effusion volumes and
exchange rate5 were identical at both knees, then recirculation of
RISA accounts for approximately I%, 6%, and 18% of synovial fluid
activity in the injected knee at 24, 48, and 72 hours, respectively.
effusion and a similar contralateral knee effusion in 1
consenting individual with seronegative rheumatoid
arthritis (RA patient 9). Serial plasma samples were
also studied. The history and physical findings of both
effusions were essentially identical, and the synovial
fluid leukocyte counts differed by <lo% (28,130 and
30,400). Synovial fluid RISA in the contralateral,
uninjected knee was 15, 55. 62, and 74% of plasma
activity 1, 24, 48, and 72 hours, respectively, after
injection. Assuming that the RISA transsynovial exchange kinetics and synovial fluid RISA distribution
volumes were approximately equal in both knees, then
recirculation of RISA from peripheral blood constituted <1% of synovial fluid RISA activity 24 hours after
injection. At 48 and 72 hours, this figure increased to
6% and 18%, respectively (see Figure 6). RlSA recirculation was thus an insignificant factor in determining
synovial fluid RISA activity during the 24-hour observation period used for the present study.
DISCUSSION
A simple and accurate measure of intraarticular
volume provides a useful tool for studying the local
physiology of joint disease. In this report we have
447
introduced an isotopic method for quantifying intraarticular volume in the knees of patients with rheumatoid arthritis or osteoarthritis. Volumes derived by
RISA distribution have been contrasted with volumes
obtained at aspiration, and distribution volumes have
enabled us to quantify the clearance of albumin and
iodine from human synovial effusions.
Previous work in our laboratory on the kinetics
of transsynnovial solute exchange included volume
considerations (13,14). Isotonic saline was injected
into normal and diseased knees while solute entry and
exit were evaluated by serial sampling. Those early
studies with artificial effusions revealed that variations
in injected volume significantly affected the exchange
rates of solutes crossing the synovial tissue barrier.
The experiments described in this report extend and
refine those early observations by considering the
volumes and exchange rates of natural synovial effusions unchanged by saline injection or by serial aspiration.
These studies were designed to minimize distortion of the baseline pathophysiologic condition. All
effusions were clinically stable prior to study, and
synovial fluid volume and hydrostatic pressure were
maintained by saline replacement of the initial synovial fluid aspirate. All patients remained ambulatory,
and medication regimens were unchanged throughout
the period of observation. We assume, therefore, that
the synovial effusions remained in a steady state,
clinically and physiologically, throughout the period of
study.
Measurement of volume by isotope dilution
requires a marker which is physiologically inert at the
studied site. Because albumin is the most abundant
protein in both plasma and synovial fluid and is critical
in the regulation of transvascular fluid balance, we
chose radiolabeled albumin for measurements of intraarticular volume. We have assumed that exogenous
RISA is handled like endogenous albumin within the
joint space, i.e., without substantial local aggregation,
degradation, nonspecific binding, or consumption by
joint tissues. These assumptions are supported by
sucrose density gradient analysis, which indicates that
synovial fluid RISA does not become aggregated within the joint, and by protein precipitation studies, which
suggest that synovial fluid 13'1 radioactivity remains
bound to albumin within the knee. In addition, studies
with scintigraphic imaging indicate that RISA does not
diffuse into periarticular tissues. These results suggest
that the injected RISA behaves like monomeric endogenous albumin and constitutes a stable and appropriate
marker for defining intraarticular volume.
448
Solute distribution and clearance from joints
reflects organ-level physiology. We presume that the
articular tissue, although histologically diverse, may
be approached as a single functional unit isolated from
adjacent tissues by a relatively impermeable joint
capsule. Images obtained by scintigraphic scanning
support our view that the joint constitutes a discrete
anatomic and functional unit (Figure 4). The isotope
markers used for these studies, 1231and RISA, are
highly water-soluble and easily distribute throughout
the articular compartment. Unlike xenon (IS), neither
is preferentially sequestered in periarticular fatty
stores.
Recirculation of injected radionuclide from
plasma to synovial fluid, after initial clearance from
synovial fluid, has been considered to be a significant
obstacle in studies of articular clearance kinetics (16).
Through study of one individual’s bilateral knee effusions we determined that, at the doses of isotope used
in these studies, recirculation constitutes <1% of
detectable radioactivity over the knee, up to 24 hours
after injection.
Serial determinations of apparent RISA distribution volume were made in preliminary studies and
revealed that volumes expanded for up to 24 hours and
were stable thereafter. Scintigraphic imaging of intraarticular RISA did not reveal changes in the geometry of RISA distribution after 24 hours. On the basis
of these findings, the calculated distribution volume
VR24 was chosen as the most physiologically appropriate volume for characterizing synovial effusions. We
believe VR24 reflects the total volume of synovial fluid
continuous with the interstitial fluid in adjacent synovial tissues. Since tight junctions are not observed
between the synovial lining cells, synovial fluid may
be considered a fluid-phase extension of the extracelM a r matrix in synovial tissues (17). Volumes obtained
by isotope distribution will therefore vary with the
extent to which the isotope marker has equilibrated
within intracapsular tissues. Our findings indicate that
radiolabeled albumin completes this process by 24
hours and that distribution volumes remain constant
thereafter.
Average aspirated synovial fluid volume, VA,
substantially underestimates the intraarticular volume
defined by RISA distribution. The aspirated volume of
synovial fluid in OA effusions was generally less than
half the volume obtained by RISA distribution. The
aspirated synovial fluid volume from rheumatoid effusions was an even smaller and more variable fraction
WALLIS ET AL
of VR24 (Figure 1). Aspirated volume underestimates
intraarticular distribution volume because it necessarily neglects the volume of synovial tissue interstitial
fluid. The interstitial portion of the intraarticular volume is of considerable physiologic interest since it
represents the site where nutrient exchange between
plasma and synovial fluid occurs. Spuriously low
aspirated volume readings in some effusions may have
resulted from obstructing rice bodies (18), synovial
plicae (19), or popliteal cysts sequestered by one-way
valves (20). Factors such as posterior recesses and the
complexity of knee joint geometry clearly render additional portions of the intraarticular space inaccessible
for sampling.
Intraarticular volume determination by dilution
of injected marker has been described previously.
Rekonen et al (2 1) found average intraarticular apparent distribution volumes of 49 ml in the knee effusions
of 17 individuals with rheumatoid arthritis, using a
small solute (II3indium) that was allowed to distribute
within the knee for 2 minutes before resampling.
Wigginton et a1 (22) evaluated methotrexate distribution within 4 rheumatoid effusions by serial arthrocentesis, and describea a mean intraarticular apparent
distribution volume of 69 ml. These figures are lower
than volumes obtained by RISA dilution in our investigations. We suspect that this difference chiefly reflects
selection of an inadequate time for full distribution
throughout the intracapsular space, although differences in the study populations may also be important.
In this report we have introduced a method of
quantifying intraarticular volume. Determinations of
intraarticular volumes and isotope removal rate constants have enabled us to derive the iodine clearance
and albumin clearance from relatively unperturbed
synovial effusions in vivo. Aspirated volumes of synovial fluid were considerably less than intraarticular
volume defined by isotope distribution. Mean iodine
clearance in rheumatoid effusions was comparable
with that found in osteoarthritis effusions, while mean
albumin clearance was significantly greater.
ACKNOWLEDGMENTS
We thank the patients who generously consented to
participate in these studies, many kind physicians for patient
referrals, Chris Pickerel1 for able technical assistance, and
Nisa Rachie for skillful word processing.
VOLUME AND CLEARANCE IN EFFUSIONS
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