214
Treatment of Canine Embolic Pulmonary
Hypertension With Recombinant Tissue
Plasminogen Activator
Efficacy of Dosing Regimes
Frank Shiffman, PhD, John Ducas, MD, FRCP(C),
Peter Hollett, MD, FRCP(C), Esther Israels, MD, David Greenberg, MD, FRCP,
Robert Cook, MSc, and Richard M. Prewitt, MD, FRCP(C)
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We investigated effects of two dosing regimes of recombinant tissue plasminogen activator
(rt-PA) and sodium heparin on pulmonary thrombolysis in a canine model of pulmonary
hypertension, induced by injection of radioactive blood clots. By continuously counting over
both lung fields with a mobile gamma camera, we correlated rate and extent of pulmonary
thrombolysis with corresponding pulmonary hemodynamics. Treatment with heparin, over a
3-hour interval, did not result in significant thrombolysis or in a decrease in mean pulmonary
artery pressure (PAP). In contrast, rt-PA caused marked pulironary thrombolysis. While total
clot lysis was similar when 1 mg/kg rt-PA was infused over 15 (rt-PA15) or 90 (rt-PA90) minutes
(47% and 42%, respectively), rate of lysis during infusion was markedly increased with rt-PA15
(56% vs. 27%/hr, p<O.OOl). Corresponding to the increased rate of thrombolysis with rt-PA15,
relative PAP decrease was greater at 15 and 30 minutes. At 4 hours, PAP decreased most with
rt-PA90. However, two of the six dogs given rt-PA15 had an increase in PAP and lung
radioactivity 1 hour after rt-PA. This was associated with dislodgment of a previously trapped
clot. These results suggest that rt-PA may be appropriate therapy for pulmonary embolism and
support further studies designed to optimize dosing regimes. (Circulation 1988;19:214-220)
R ecent clinicall-5 and basic6-8 studies have
demonstrated the efficacy of recombinant
tissue plasminogen activator (rt-PA) in
inducing thrombolysis. Two prospective, randomized clinical studies demonstrated that rt-PA may
be superior to streptokinase in treatment of coronary thrombosis. 12 In these two studies, while the
decrease in systemic fibrinogen levels was greater
with streptokinase, bleeding complications, usually
at puncture sites, were similar with rt-PA and
streptokinase.
While numerous studies have investigated the effects
of rt-PA in acute coronary occlusion due to thrombosis, only a few have studied the effects of rt-PA in
From the Departments of Medicine, Pharmacology, and Radiology, University of Manitoba Health Sciences Centre, Winnipeg, Manitoba, Canada.
Supported by Medical Research Council of Canada. J.D. is a
Manitoba Health Research Council Scholar, and R.M.P. is the
Manitoba Heart Foundation Research Professor.
Address for correspondence: Dr. Richard M. Prewitt, Department of Medicine, Health Sciences Centre, 700 William Avenue,
F223, Winnipeg, Manitoba R3E OZ3, Canada.
Received December 21, 1987; revision accepted March 24, 1988.
pulmonary embolism.9"0 The present study was
designed to assess the effect of rt-PA on pulmonary
thrombolysis in a canine model of radioactive autologous clot embolization. By continuously imaging over
both lung fields with a mobile gamma camera, we
correlated rate and extent of clot lysis with corresponding pulmonary hemodynamics. Finally, because previous work has suggested that a given dose of rt-PA
may be more effective in inducing thrombolysis when
given over a short period of time,8 we compared the
relative efficacy of rt-PA given over 15 minutes versus
the same total dose infused over 90 minutes.
Materials and Methods
Eighteen dogs (15-27.5 kg) were anesthetized
with pentobarbital (30 mg/kg i.v.) and supplemented as required to maintain apnea. Each dog
was mechanically ventilated in the supine position
via an endotracheal tube with 100% 02 at a tidal
volume of 20 ml/kg. Rate was adjusted to maintain
Paco2 between 35 and 45 mm Hg. Metabolic acidosis was treated as required with sodium bicarbonate
to maintain arterial pH greater than 7.25. A catheter
Shiffman et al rt-PA in Pulmonary Embolism
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was inserted into the right femoral artery. Measurements of blood pressure were obtained from this
catheter, and 200 ml blood was drawn for formation
of autologous clot. A thermistor-tipped, flowdirected Swan-Ganz catheter (Electro Catheter, Rahway, New Jersey) was inserted via the external
jugular vein and positioned in the proximal pulmonary artery. Measurements of cardiac output (CO)
and mean pulmonary artery pressure (PAP) were
obtained from this catheter. A second Swan-Ganz
catheter was placed in the right ventricle to obtain
measurements of right ventricular (RV) pressure. A
pigtail catheter (Cordis, Miami, Florida) was inserted
via the left femoral artery into the left ventricle for
measurement of left ventricular end-diastolic pressure (LVEDP). Each catheter was connected to a
Statham P23 (Gould, Oxnard, California) transducer
leveled to midchest. Transducer output was displayed
on a 12-channel Electronics for Medicine oscillograph
(PPG Biomedical Systems, Pleasantville, New York).
A third Swan-Ganz catheter was positioned in the
right atrium for injection of saline boluses for determination of CO by computer (Columbus Instruments,
Columbus, Ohio). An intravenous line, for clot injection, was inserted into the right femoral vein. Figure 1
illustrates the experimental preparation. The surgical
procedures were generally completed within 1 hour.
During the experiment, normal saline was infused at
approximately 100 ml/hr.
Radioactive Autologous Blood Clot Formation
A low specific activity technetium-99m sulfur
colloid preparation was created by boiling 3.0 ml IN
HCI, 3.0 ml Na2S203-5 H20, and 1.0-1.5 GBqs
technetium-99m pertechnetate in 9.0 ml saline for
3.5 minutes. Technetium-99m sulfur colloid (TSC)
was chosen to label clot because of its known
affinity for fibrin strands and because the small
particles (0.1 ,um) are rapidly cleared when released
Endotracheal
Tube
Infusion Line
\
Vi//
Pulmonary Artery Cath.
Right Atrial Cath.
Right Ventricle Cath.
Blood
Pressure
Cath.
Left Ventricle Cath.
Normal Saline
Radioactive
Clot
FIGURE 1. Diagram of experimental preparation. (For
details, see text.)
215
by the reticuloendothelial system (serum t112 approximately 2 minutes), making background correction
unnecessary.11'12 After ice-bath cooling for 5 minutes, 0.3 ml human serum albumin and 8.0 ml phosphate buffer were added. High-quality preparations
were confirmed with instant thin layer chromatography in methyl ethyl ketone (98.4 + 0.3%).
Autologous clot was formed by slowly dripping
100 ml freshly drawn unheparinized dog blood with
7.0 ml (350 MBqs) TSC and 10,000 units (10 ml) of
thrombin into a shielded 500-ml Pyrex beaker. The
mixture was allowed to stand for 2 hours until the
clot had a "Jello-like" consistency. The serum was
decanted and discarded. The low specific activity
TSC ensured a large number of particles with adequate distribution in the clot matrix. The use of a
small volume of TSC and the glass-walled container
were necessary to develop a solid thrombus. The
clot was then cut into approximately l-ml aliquots
and loaded into 60-ml syringes before injection.
Protocol
After obtaining baseline measurements, autologous clot was injected via the femoral vein intravenous line and flushed in with normal saline. It was
infused gradually over approximately 30 minutes
until PAP rose to approximately 55 mm Hg. The
dogs were allowed to stabilize for approximately 30
minutes. During this period, there was a small
decrease in PAP. After clot injection, hemodynamic
measurements were obtained at 10-minute intervals.
The preparation was considered stable when measurements of mean blood pressure (BP), CO, and
PAP varied less than 10%o on two consecutive measurements. After documenting stability, the dogs
were then randomly selected for intravenous treatment with bolus sodium heparin at 100 IU/kg (infused
over 15 minutes) or rt-PA (Genentech, Toronto,
Ontario, Canada) at 1.0 mg/kg given over 15 or 90
minutes through the jugular infusion line. At the
beginning of the study, 18 slips of paper each specifying a given treatment (6 rt-PA15, 6 rt-PA0, 6 heparin) were placed in a container. The type of treatment
was chosen at the point of randomization by blindly
selecting one of these slips. Each treatment was
immediately followed with sodium heparin infusion
at 10 IU/kg/hr for the remainder of the experiment.
Hemodynamic measurements (BP, PAP, CO,
RVEDP, and LVEDP) were obtained and repeated
at the following times: baseline, before clot injection; after embolization, immediately before treatment; and at 15, 30, 60, and 90 minutes and 2 and 3
hours after onset of drug infusion.
Assessment of Pulmonary Thrombolysis
Monitoring of lung and abdominal activity was
achieved with a Picker Dyra IV mobile gamma
counter (Picker International, Winnipeg, Manitoba,
Canada) with a parallel hole collimator coupled to
an MDS A2 mobile computer (Medtronic of Canada,
Richmond, BC, Canada). Four-hour dynamic acqui-
216
Circulation Vol 78, No 1, July 1988
TABLE 1. Hemodynamic Effects of Embolization
PAP (mm Hg)
CO (/min)
RVEDP (mm Hg)
BP (mm Hg)
LVEDP (mm Hg)
3.2 ±0.3
137-+-4
13.9±0.5
3.8 +0.5
Before embolization
5.7 ± 0.5
128 ±4
45.4± 1.0*
2.0 ± 0.2t
7.5 +1.2t
After embolization
5.0 +0.5
Values are mean ± SEM.
BP, blood pressure; PAP, pulmonary artery pressure; CO, cardiac output; RVEDP, right ventricular end-diastolic pressure; LVEDP,
left ventricular end-diastolic pressure.
*p<0.0005, tp<0.001, tp<0.01.
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sition was in a 64 x 64 matrix at a 120 sec/frame rate.
Thus, an image was obtained every 2 minutes over the
course of the experiment. Regions of interest were
placed about the lung fields and liver. To assess total
pulmonary thrombolysis, counts in the lungs were
summed over the 10 minutes just before administration of therapy and were compared with a decaycorrected image from the final 10 minutes. To assess
rate of pulmonary thrombolysis, the pulmonary timeactivity curves were normalized to the maximum
counts in the lung fields that always occurred near the
end of the clot infusion. After obtaining the decaycorrected time-activity curve, a marker was placed at
the onset and the end of drug infusion, and both linear
and exponential best-fit curves between these coordinates were generated by the computer. Because there
was no significant difference in description of the data
by either equation, a linear model was chosen. The
mean + SD correlation coefficients in dogs treated
with rt-PA15, rt-PA90, and heparin were 0.98-+±0.02,
0.98±+ 0.02, and 0.89±+ 0.03, respectively. Thus, a
slope" of the time-activity curve could be defined to
estimate the rate of clot lysis during drug infusion.
This relation is expressed in terms of the percent
decline of total lung counts per hour. In one dog that
received rt-PA over 90 minutes, because of dog and/or
camera movement during infusion, we were unable to
determine the slope of the time-activity curve. However, total pulmonary thrombolysis was assessed in
this dog.
In both rt-PA-treated groups, the final hour of
clot lysis closely approximated treatment with heparin alone. To determine when the effects of rt-PA
were clearly separate from that of heparin, a line
representing the mean rate of clot lysis for heparin
was back projected on each experimental line. The
point at which the rt-PA line approached within 2
SD of the heparin control line was taken as the point
at which clot lysis due to rt-PA ceased.
groups at each time interval by a one-way ANOVA.
If any one-way or two-way ANOVA were signifi-
Data Analysis
rt-PAw-treated
The total clot lysis, rate of clot lysis during
infusion, and time of clot lysis after infusion were
compared between groups by a one-way ANOVA.
If this were significant (p<0.05), Student-NewmanKeuls test was used to determine which means
differed. Hemodynamic parameters were analyzed
for change with embolization and change with time
after onset of treatment by a two-way ANOVA.
These hemodynamic measurements, plus the change
in PAP from infusion onset, were compared between
13
14
15
16
17
cant (p<0.05), Student-Newman-Keuls test was
used to determine which points were different.
Results
Table 1 illustrates mean hemodynamic values
before and after embolization for all 18 dogs. Embolization was associated with a marked increase in
PAP (p<0.0005) and RVEDP (p<0.01) and a
decrease (p<0.001) in CO. BP and LVEDP remained constant with embolization.
Table 2 illustrates individual and mean effects of
heparin, rapid administration of rt-PA (rt-PA15), and
short-term infusion of rt-PA (rt-PA9,) on rate of clot
lysis. The rate of clot lysis observed during treatment and the values obtained after rt-PA was disTABLE 2. Rate of Pulmonary Thrombolysis
Clot lysis (%/hr)
Dog
During treatment
After treatment
Heparin-treated
1
2
3
4
5
6
Mean+SEM
rt-PA15-treated
7
8
9
10
11
12
Mean ± SEM
1.5
4.8
3.1
2.6
2.6
1.7
2.7+0.5
57.6
47.5
52.6
42.1
66.6
70.6
56.2 ± 4.5*
0.4
8.4
0.7
6.3
3.6
7.2
4.4± 1.4
16.4
0.7
27.4
0.4
29.9
8.6
37.1
8.1
21.8
2.5
Mean±SEM
26.5±3.5t
4.1+1.8
rt-PA15, rapid rt-PA administration; rt-PAgo, short-term rt-PA
infusion.
*p<O.001 comlpared with heparin and
tp<0.001 compared with heparin.
rt-PA9u;
Shiffman et al rt-PA in Pulmonary Embolism
TABLE 3. Individual Times in Minutes of Persistent Clot Lysis
After Discontinuing rt-PA15 Treatment (Six Dogs) or rt-PA90
Treatment (Six Dogs)
rt-PA15
rt-PA90
37
17
48
25
58
105
Mean±SEM 48±13*
rt-PA15, rapid rt-PA administration;
-7
4
0
32
-23
-5
0±7
infusion.
rt-PA90,
short-term rt-PA
*p<0.01 compared with rt-PAgo.
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continued and the rate of clot lysis became relatively constant are given. In dogs treated with heparin,
rate of lysis was minimal and constant over the 3-hour
treatment interval. In contrast, rt-PA caused marked
pulmonary thrombolysis. As illustrated in Table 2,
compared with heparin, rt-PA90 increased the rate of
clot lysis (p<O.OO1) during the 90-minute infusion
interval. Shortly after rt-PA was discontinued, there
was a marked attenuation in rate of clot lysis. As
illustrated in Table 3, before or shortly after rt-PA90
was discontinued, rate of thrombolysis became constant and similar to that in the heparin group.
Compared with the other two groups, rt-PA15
achieved the most rapid (p<0.001) rate of clot lysis.
As depicted in Table 2, during infusion, rate of clot
lysis with rt-PA15 was two times as great as with
rt-PA90 and 20 times greater than with heparin. As
with rt-PA90, after rt-PA15 was discontinued, there was
a marked decrease in rate of clot lysis. On average, 48
minutes after rt-PA15 was discontinued, the rate of
lysis became constant and was similar to that observed
with heparin (Table 3). Figure 2 plots typical timeactivity curves for each treatment regime. Note the
effectiveness of rt-PA in inducing pulmonary thrombolysis. During infusion, rate of clot lysis was relatively constant. Also illustrated in each condition are
time-activity hepatic-uptake curves. Note the direct
relation between pulmonary thrombolysis and hepatic
uptake. Similar relations were noted in each dog.
Figure 3 compares images obtained over the 10 minutes just before treatment with the time decay-corrected images obtained over the final 10 minutes.
Note the marked difference between the rt-PA regimes
and heparin in inducing pulmonary thrombolysis. Figure 4 plots mean + SEM results and illustrates the
effects of heparin and rt-PA on total extent of clot
lysis over 3 hours. Compared with heparin, pulmonary thrombolysis was markedly increased with rt-PA
(p<O.OOl). Despite the different rates of pulmonary
thrombolysis observed during rt-PA15 and rt-PA.0 infusions, extent of clot lysis was similar.
Table 4 depicts mean + SEM values and illustrates
hemodynamic effects of embolization and treatment.
In correspondence with increased thrombolysis with
rt-PA, pulmonary hemodynamics improved. Note that
217
100.0
Lung Breakdown 5 %
LUver
0.0
0.011
HEPARIN
1.439
'o
m
-5
a-
rtPA 15
Time (seconds x 10')
FIGURE 2. Time-activity curves illustrating pulmonary
thrombolysis during infusion of heparin and during and
after rt-PA9% and rt-PA15 infusion. Also illustrated are
corresponding hepatic uptake curves.
while CO and LVEDP remained similar between
groups over time, PAP decreased in dogs given rt-PA.
Corresponding to the initial, rapid rate of pulmonary
thrombolysis with rt-PA15, there was a marked
decrease in PAP. Compared with heparin and rt-PA%0,
at 15 (p<0.01) and 30 minutes (p<0.005, p<0.025),
PAP decreased most with rt-PA15. Also, at 30 minutes, in a comparison among groups, PAP was significantly less with rt-PA15 than with heparin (p<0.025).
From 1 to 3 hours after onset of treatment, the PAP
for both rt-PA groups was less than with heparin
(p<0.001). From 90 minutes to the end of the study,
PAP was less with rt-PA90 compared with rt-PA15
(p<0.01-0.05) and heparin (p<0.001). Also, comparing rt-PA15 with heparin, PAP was less from 30 minutes to 3 hours. In two of the six dogs treated with
rt-PA15, pressure increased after an initial decrease in
PAP. This increase was associated with clot fragments observed on nuclear images to migrate from the
inferior vena cava into the lung. This may explain the
slight increase in PAP after 1 hour in this group.
Figure 5 plots mean ± SEM PAP in each group as a
function of time. As illustrated in Table 3, note the
initial rapid decrease in PAP with rt-PA15 and the
more gradual decrease with rt-PAgo.
As depicted in Table 4, CO remained similar within
and between groups over time. In all groups, RVEDP
increased with embolization (p<0.01). Compared with
heparin where RVEDP remained constant, RVEDP
218
Circulation Vol 78, No 1, July 1988
5040-
to
30-
C1)
0-
20-
10-
HEPARIN
rtPA15
rtPA90
Treatment
FIGURE 4. Bar charts of effects of heparin, rt-PA15, and
rt-PA90 on mean±SEM clot lysis percentage.
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FIGURE 3. Images obtained over a 10-minute interval
before treatment and time decay-corrected images obtained
over the final 10 minutes for the three treatment regimes.
decreased in both rt-PA groups from 15 minutes with
rt-PA15 and from 30 minutes with rt-PA%0. Also, comparing among groups, RVEDP was less with rt-PA90
than with heparin or with rt-PA15 from 90 minutes to 3
hours. Note that before embolization, RVEDP was
lower in the rt-PAx group than in dogs randomized to
rt-PA15. This may explain the differences in this parameter between the two rt-PA groups from 90 minutes to
3 hours. Values for LVEDP were within the normal
range and remained similar within and among groups
over time. Similarly, considering within-group comparisons, other than a small decrease in BP at 3 hours
in dogs given heparin, this parameter remained relatively stable over time.
All incision sites for catheter placement were left
open, and there was no observed difference in estimated blood loss between groups. Also, hematocrit
was measured at the beginning and end of each
experiment. While the mean values tended to
decrease with rt-PA,5 (- 13%) and rt-PA%,) (- 10%)
and remained constant with heparin (+44%), these
changes were not significantly different (one-way
ANOVA).
With respect to gas exchange, there were no differences among groups at any time. With the exception
of one dog in the heparin group, values for arterial 02
tension were always greater than 210 mm Hg.
Discussion
This study was designed to assess the efficacy of
a new thrombolytic agent, rt-PA, in inducing thrombolysis in a canine model of autologous blood clot
pulmonary emboli. Our study also tested the hypothesis that rapid administration of a given dose of
rt-PA would result in more complete clot lysis than
prolonged administration of the same dose.
We observed that compared with treatment with
heparin, rt-PA was efficacious in inducing pulmonary
thrombolysis and improving pulmonary hemodynamics. In a comparison among groups treated with
rt-PA, while extent of clot lysis was similar with
rt-PA15 and rt-PA%,, during infusion, the rate of
pulmonary thrombolysis was markedly increased
with rt-PA15. Corresponding to the rate of clot lysis,
during infusion, PAP decreased most rapidly with
rt-PA,5. As indicated, none of the treatment regimes
caused excessive bleeding. Because the majority of
deaths due to right ventricle failure and shock complicating massive pulmonary embolism occur relatively early after onset of symptoms,'3,14 the therapeutic regime that induces the most rapid pulmonary
thrombolysis is probably preferred over regimes that
have slower onsets of action.
As discussed in "Results," in two of the six
rt-PA,5 dogs, there was evidence of reembolization
and an increase in PAP 1 hour after rt-PA. While this
observation may support prolonged infusion of rt-PA
in our model, only small numbers are involved, and
this may represent an artifact of this preparation.
That is, radioactivity was sometimes detected in the
inferior vena cava. This must represent trapping of
Shiffman et al rt-PA in Pulmonary Embolism
219
TABLE 4. Hemodynamic Effects of Embolization and Treatment
Measurement Treatment Baseline
Heparin 14.0±0.8
PAP
rt-PA15 14.8± 1.0
rt-PA90 12.9±0.5
Time
Postembolization 15 minutes 30 minutes
42.8± 1.6
44.2± 3.6A
40.2±1.7
33.0 ± 2.9B
38.2±2.1
28.1 ± 2.8a
2 hours
11/2 hours
1 hour
3 hours
37.0± 2.0 37.8± 1.7 37.5± 1.8 38.3 ± 2.3
22.0 ±2. lb 24.5±2.7b 22.8 ±2.3b 22.6± 2.7b
38.8± 1.5c 32.3±+1.4D 21.7±1.7b,E 16.0± 1 lb,c 14.8± 1 Ib,c 14.9+1.3b,d
3.8±1.4
5.8 ±2.0
4.5 2.7
4.4±2.0
3.0±2.2
5.3 ± 2.3
10.9±1.6e 19.4 ± 3.5f 22.3 +2.7 23.0± 2.48 21.5 ± 2.69 21.7 2.08
...
rt-PA15
2.8±1.5
9.2±2.3 20.2 2.3g 25.8+1.89 27.1± 1.49 26.9±1.29
...
rt-PA90
1.9±0.2
1.9±0.2
1.9±0.2
1.8±0.2
2.2±0.5
2.5±0.7
3.8±0.7
Heparin
CO
1.3±0.1
1.3±0.1
1.3±0.1
1.3±0.1
2.2±0.5
2.2±1.0
3.1±0.3
rt-PA,5
1.4 ±0.1
1.6±+0.3
1.7±+0.3
0.3
1.8±0.2
1.8
1.9±0.3
2.8
±0.6
rt-PA90
5.7±0.7
6.6±+ 1.1
6.1±0.8
5.6± 1.0
8.3 2.4
7.6±2.4
3.7±0.8
Heparin
RVEDP
4.5±0.7
4.5±+ 0.7 5.3 ±+0.6 5.2±0.5
5.0±0.7
5.4 + 0.9
5.7 ± 0.4
rt-PA15
4.1±1.0
5.6± 1.0
2.8±0.9h 2.3 ±1.oi 2.6±0.5i 2.1 ±0.6'
7.6±2.2F
rt-PA9% 2.5±0.4d
PAP, pulmonary artery pressure; APAP, mean PAP; CO, cardiac output; RVEDP, right ventricular end-diastolic pressure.
Within-group comparisons: Ap<O.Ol compared with all other times; Bp<0.005 compared with 30 minutes-3 hours; Cp<O.001 compared
with 30 minutes-3 hours; Dp<O.00l compared with 1-3 hours; Ep<0.001 compared with 1'/2-3 hours; Fp<0.005-0.05 compared with 30
minutes-3 hours.
Between-group comparisons: 5p<O.O2s compared with heparin; bp<0.001 compared with heparin; cp<O.Ol compared with rt-PA15;
dp<o.o5 compared with rt-PA15; ep<0.01 compared with heparin and rt-PA90; fp<0.005 compared with heparin and p<0.025 compared
with rt-PA90; gp<0.001 compared with heparin; hp<o.os compared with heparin; ip<0.025 compared with heparin and p<0.05 compared
with rt-PA15; jp<0.01 compared with heparin and p<0.025 compared with rt-PA15.
lAPAP
Heparin
...
41.8 1.8c
.
...
...
2.6+0.6
1.7±0.1
1.9+0.3
7.8±1.9
8.1 ± 0.6c
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clot fragments that subsequently dislodged and reembolized in the two dogs discussed above.
The thrombolytic efficacy of rt-PA has previously
been demonstrated in both basic and clinical studies. A recent clinical study of patients with acute
myocardial infarction reported that for the doses
used, rt-PA was twice as effective as streptokinase
in inducing acute coronary thrombolysis.' Other
clinical1-5 and basic6 studies have confirmed the
effectiveness of rt-PA in acute coronary thrombolysis. Also, recent studies have reexamined the
role of lytic therapy in venous thromboembolism.
Experimental studies in animal models7'8'15 and
initial case reports10 and clinical studies93'6 indicate
that rt-PA may be an excellent drug for treatment of
venous thromboembolism.
One study used rabbits to investigate the effects
of different dosing regimens of rt-PA on thrombolysis of radioactive jugular vein thrombi.8 The
same dose of rt-PA infused over 15, 30, 60, and 240
minutes produced 96%, 88%, 87%, and 36% thrombolysis, respectively. While the 1-hour infusion of
rt-PA increased bleeding and decreased a2antiplasmin levels, the same dose infused over 15
and 30 minutes did not affect these parameters. The
present study describes similar but not identical
effects between rt-PA infused over 15 and 90 minutes. While the rate of pulmonary thrombolysis was
much greater during rt-PA,5 infusion, there was
evidence of reembolization in two of the six rt-PA15
dogs, and final extent of lysis was similar between
rt-PA15 and rt-PA90. The difference in results between
studies may be explained by the obvious differences
in experimental design. However, results from both
studies suggest that rapid infusion of rt-PA may be
the preferred method of administration.
A recent clinical study used rt-PA in treatment of
patients with pulmonary embolism. Goldhaber et a19
treated 36 patients with documented pulmonary
embolism. rt-PA (50 mg) was infused over the first 2
hours, followed by angiography and additional rt-PA
(40 mg/4 hr) as required. The quantitative score, an
index of vascular obstruction, improved 21% by 2
hours and 49% by 6 hours. However, PAP only
decreased slightly (p<0.05) after rt-PA therapy, from
50-
40-
E
/
20
10-
End
Start Infusion rtPA15
0
1.0
15
End
rtPA90
20 2.5 3.0
4.0
Time hours)
FIGURE 5. Plot of effects of treatment of mean pulmonary artery pressure.-, A, and m, treatment of heparin,
rt-PA9%, and rt-PA15, respectively.
220
Circulation Vol 78, No 1, July 1988
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22 to 18 mm Hg, and values for CO were not
reported. The relatively small amount of clot lysis
that occurred over the first 2 hours may be due to the
slow infusion rate of a relatively low dose of rt-PA.
The same authors subsequently extended their observations by studying an additional 11 patients with
pulmonary embolism. i6
In contrast to the study cited above,9 acute and
short-term pulmonary thrombolysis were more rapid
and more complete in the present study where a
larger dose of rt-PA was administered more rapidly.
Corresponding to thrombolysis with rt-PA, PAP dramatically decreased. As depicted in Table 3, pulmonary thrombolysis continued for a mean time of 48
minutes after rt-PA15 was discontinued. Therefore,
effective thrombolytic time with rt-PA15 was approximately 60 minutes. As illustrated in Figure 5, PAP
continued to decrease in this group for approximately 1 hour after onset of treatment. Subsequently, when rate of clot lysis was minimal and
similar to that observed in heparin-treated dogs, PAP
remained relatively constant. If reembolization had
not occurred in two dogs, PAP would have been
lower. Because the circulating half-life of rt-PA is
reported to be short (approximately 5 minutes), these
results suggest protection of both fibrin-bound rt-PA
and plasmin from their inhibitors. A study using
rabbits also reported sustained lysis of radioactive
jugular vein thrombi after bolus injection of rt-PA.7
In contrast to the 15-minute infusion of rt-PA, the
rate of clot lysis and change in PAP became similar
to the heparin group when the infusion of rt-PA
ceased in dogs given rt-PA over 90 minutes. In those
dogs treated with heparin, there was trivial thrombolysis and PAP remained relatively constant over
the 3-hour treatment interval. The failure for CO to
increase in dogs treated with rt-PA may be explained
by relative hypovolemia. That is, while RVEDP
remained elevated in dogs treated with heparin, this
parameter decreased in those given rt-PA.
While there is some debate, most physicians agree
that when circulatory compromise complicates pulmonary embolism, thrombolytic therapy may be
indicated. Results from the present study and those
cited above suggest that rt-PA may be an excellent
drug for treatment of pulmonary thromboembolism.
Further, results from the present study indicate that
the method of administration of rt-PA may significantly affect the dynamics of thrombolysis. We
emphasize caution in extrapolation of our results to
the clinical area because these findings were in an
anesthetized canine preparation with exogenously
produced autologous blood clots. However, these
results support further prospective studies designed
to optimize dosing regimens of rt-PA.
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KEY WORDS * recombinant tissue plasminogen activator
pulmonary embolism * pulmonary hypertension
Treatment of canine embolic pulmonary hypertension with recombinant tissue
plasminogen activator. Efficacy of dosing regimes.
F Shiffman, J Ducas, P Hollett, E Israels, D Greenberg, R Cook and R M Prewitt
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Circulation. 1988;78:214-220
doi: 10.1161/01.CIR.78.1.214
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