(Circulation. 2000;102:238.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Ultrasound Imaging–Guided Noninvasive Ultrasound Thrombolysis
Preclinical Results
From the Tel Aviv Sourasky Medical Center (U.R.) and Angiosonics Ltd R&D Laboratories (V.F., E.K., I.F., Y.E.), Tel Aviv, and the Meir Medical Center, Kfar Saba (J.B.), Israel.
Correspondence to Uri Rosenschein, MD, Catheterization Laboratory, Department of Cardiology, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv 64239, Israel. E-mail urosenschein{at}angiosonics.co.il
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Abstract |
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Background—Catheter-based therapeutic ultrasound thrombolysis was recently shown to be effective and safe. The purpose of this work was to study the safety and efficacy of external high-intensity focused ultrasound thrombolysis guided by ultrasound imaging in experimental settings.
Methods and Results—A therapeutic transducer was constructed from
an acoustic lens and integrated with an ultrasound imaging transducer.
In vitro clots were inserted into bovine arterial segments
and sonicated under real-time ultrasound imaging guidance in a water
tank. With pulsed-wave (PW) ultrasound, the total sonication time
correlated with thrombolysis efficiency
(r2=0.7666). A thrombolysis
efficiency of 91% was achieved with optimal PW parameters
(1:25 duty cycle, 200-µs pulse length) at an intensity
(Ispta) of >35±5 W/cm2. Ultrasound imaging
during sonication showed the cavitation field as a spherical cloud of
echo-dense material. Within <2 minutes, the vessel lumen evidenced
neither residual clot nor damage to the arterial wall. On
serial filtration, 93±1% of the lysed clot became subcapillary in
size (<8 µm). In vitro safety studies, however, showed
arterial damage when an Ispta of 45
W/cm2 was used for periods of 
300 seconds.
Conclusions—External high-intensity focused ultrasound
thrombolysis using optimal PW parameters
for periods of 
300 seconds appears to be a safe and effective method
to induce thrombolysis. The procedure can be guided by
ultrasound imaging, thereby allowing the monitoring of therapy.
Key Words: thrombolysis • ultrasonics
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Introduction |
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Thrombosis in the cardiovascular system is the leading cause of mortality and morbidity in the western world. The clinical management of vascular thrombosis presents a therapeutic challenge, despite the recent advances in thrombolytic and antiplatelet agents.
Clinical experience with catheter-based therapeutic ultrasound has shown that acoustic energy has the ability to induce effective thrombolysis without injuring the surrounding vessel.1 2 The potential therapeutic use of external high-intensity focused ultrasound (HIFU) was first explored by Lynn et al in 1942.3 They demonstrated that HIFU can induce localized tissue damage at a focal point within the body with no effect on the surface or on the overlying or surrounding tissue. Over the past few years, therapeutic HIFU has been successfully used in neurosurgery, ophthalmology, urology, and oncology.4 5 6 7
In an earlier feasibility study, we showed that the use of focused shock waves as a source of acoustic energy provided effective thrombolysis with no damage to the artery.8 However, shock waves are difficult to control, whereas monochromatic ultrasound allows better control of the operating parameters. Thus, the purpose of the present work was to study the safety and efficacy of HIFU thrombolysis guided by ultrasound imaging in experimental settings.
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Methods |
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Therapeutic Ultrasound Transducer
The therapeutic transducer consists of 1–3 piezo-composite material designed as a spherical ring (94-mm diameter, 70-mm radius of curvature). The acoustic lens has a focal point 45 mm from the transducer surface (Angiosonics Ltd). The focal point (-6 dB), measured below the cavitation threshold with a calibrated hydrophone (sprh-s-100, SEA), is tubular (12±1x1.8±0.2x1.8± 0.2 mm). The choice of frequency was a balance between the different inherent properties of low- and high-frequency ultrasound. At lower frequencies, ultrasound has a lower cavitation threshold and less attenuation in tissue, but the longer wavelength dictates the need for a larger focal area. At higher frequencies, the cavitation threshold and tissue attenuation are higher, but a smaller focal area can be obtained with shorter wavelength. As a result, the frequency of 500 kHz was used to accommodate the predetermined dimensions of the focal area. The transducer was driven by a pulsed-wave (PW) generator incorporated with a linear amplifier (Angiosonics Ltd). Power was monitored by a real-time peak pulse power meter (Angiosonics Ltd).
An ultrasound imaging transducer (7.5-MHz mechanical annular array) was integrated into the center of the therapeutic transducer in a concentric configuration. Real-time ultrasound imaging allowed identification of the artery and clot and monitoring and control of the cavitation activity and progress of thrombolysis.
In Vitro Studies
Experimental Procedure
Fresh bovine blood (95 mL) was mixed with 7.6% sodium citrate
solution (5 mL) and kept at 4°C for up to 3 days. Coagulation was
performed by mixing the citrated bovine blood (8 mL) with 1%
CaCl2 solution (0.08 mL) in a plastic tube
(5.5 mm in diameter). The clots were incubated at 37°C for 2
hours and kept overnight at 4°C. Before the experiment, the clots
were separated from the serum on a 150-µm nylon filter (Whatman) and
weighed (AS-120, OHAUS). This method yielded a standard clot weight of
333±47 mg (n=600).
Clots were inserted into fresh bovine carotid artery segment
(40±2 mm long with a 7±2-mm diameter). The artery-clot
preparations were mounted on a U-shaped frame connected to an X-Y-Z
positioning device (ZUK Ltd) and immersed in a water tank (28x18x21
cm) filled with degassed, deionized water (NTR Systems) (Figure 1
). The artery-clot preparations were
positioned with the long axis of the artery parallel to the plane of
the transducer. The desired ultrasound parameters were set
before the experiment. The artery-clot preparations were sonicated
while the mounted artery was moved through the fixed focal spot at a
predetermined speed of 0.25 mm/s from one end of the artery to the
other end.
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Each lysis experiment was performed under real-time ultrasound imaging.
After sonication, the arteries were flushed with saline. The saline and the liquefied clots were serially filtered (400-, 50-, and 8-µm filters). The filters were then weighed to determine thrombolysis efficiency and debris size profile.
The difference between the initial clot weight and the weight of clot particle on the 50-µm filter was defined as the lysed clot weight. The thrombolysis efficiency was calculated as the ratio between the lysed clot weight and the initial clot weight and expressed by percentage.
Optimization of Ultrasound Wave Parameter
Preliminary work with the continuous-wave mode had yielded very
low thrombolysis efficiency and significant damage to
the vessel wall. The use of a PW mode was studied. First, we examined
the influence of 2 variables on thrombolysis
efficiency, pulse length, and duty cycle. Then, we studied the
combinations of 5 pulse lengths (50, 100, 200, 300, and 400 µs) and 4
duty cycles (1:10, 1:20, 1:30, and 1:40). Six experiments were
performed for each set of parameters. The spatial peak time
average intensity at the focal spot (Ispta) and
the sonication time were kept constant (40 W/cm2
and 4 minutes, respectively).
After optimization of the pulse length and duty cycle, the relationship between Ispta and thrombolysis efficiency was evaluated (10 to 55 W/cm2 in increments of 5 W/cm2) by use of the optimized pulse length and duty cycle combination (200 µs and 1:25, respectively).
Safety Experiments
Freshly obtained swine arteries were exposed to 2 levels of
HIFU, Ispta of 45 and of 90
W/cm2. At each Ispta level,
sonication time was increased in 9 increments (6, 15, 25,45, 60, 120,
300, 600, and 1800 seconds) with the optimal combinations of PW
parameters (a 200-µs pulse length and a 1:25 duty cycle).
Arterial segments were sonicated at 3 points (
10 mm
apart) with each combination of Ispta and
sonication time. Three nonsonicated arteries were used as controls.
To further explore any potential damage by HIFU, swine tissue sections
(n=18, 3x3x3 cm), including skin and a section of the femoral
artery, were prepared. These tissue sections were subjected to the
safety sonication protocol previously described for the "naked"
arterial segments. Nonsonicated segments were used as
controls.
In Vivo Studies
The objective of the in vivo studies was to define the safety of
HIFU thrombolysis in vivo. According to the guidelines
set for animal research by the American
Physiological Society, adult pigs (15 to 20 kg)
were anesthetized with diazepam (1 mg/kg IM) and thiopentone (6
mg/kg IV). The pigs were intubated, placed on a Harvard respirator, and
ventilated with halothane (1.5% to 2.5%). The ECG and blood pressure
were monitored continuously throughout the procedure.
The femoral arteries were exposed to increasing levels of HIFU
with optimal PW parameters (200-µs pulse length, 1:25
duty cycle). Each artery (n=5) was sonicated at 3 points, 10 mm
apart, with the same combination of Ispta and
sonication time. For the in vivo studies, a coupling Teflon cushion
filled with saline together with gel facilitated coupling of ultrasound
and adjustment of the transducer height for the specific depth of the
artery from the skin to compensate for the fixed focal point. The
combinations were 45 W/cm2 for 25 and 45 seconds
and 75 W/cm2 for 25 and 45 seconds. After
sonication, tissue sections (3x3x3 cm) including skin, vessel, and
surrounding tissue were extracted and submitted to pathological
examination. Nonsonicated tissue sections were used as controls.
Pathological Analysis
After sonication, the areas of sonication were carefully
marked on the tissue, after which the tissues were kept in 10% neutral
formaldehyde solution. Samples were dehydrated in graded alcohol,
cleared in hydroxaminosole, and embedded in paraffin. Sections were cut
(4 µm), mounted on glass slides, and stained with
hematoxylin-eosin. Multiple sections from each spot of sonication were
histopathologically examined by an experienced pathologist who was
blinded to experimental details. The overall integrity of the vessel,
continuity of the elastic structure, and damage to the intervening
tissue were assessed. Damage to the vessel itself was scored according
to the following criteria: grade 0, none; grade 1, intimal; grade 2,
intimal and medial; and grade 3, perforation. Damage (coagulative
necrosis) to the intervening tissues was scored according to the
following criteria: grade 0, no coagulative necrosis; grade 1, small
area of coagulative necrosis but no coagulation; grade 2, moderate area
of coagulative necrosis; grade 3, large area of coagulative necrosis;
grade 4, very large area of coagulative necrosis.
Statistical Analysis
Continuous variables are expressed as mean±SD.
Semiquantitative variables are expressed as median (range). The
relationship between PW parameters (pulse length and duty
cycle) and thrombolysis efficacy was examined by
2-factorial ANOVA. The relationship between Ispta
and thrombolysis efficiency was examined by the
Mann-Whitney test.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In Vitro
Optimization of Ultrasound Wave Parameters
Thrombolysis efficiency correlated with total sonication time regardless of the PW parameters (Figure 2
). The longer duty cycle yielded better
thrombolysis efficiency (Figure 3). For example, sonication with a duty
cycle of 1:10 reached thrombolysis efficiency of
90±1%, compared with 45±2% when a duty cycle of 1:40 was used
(P<0.0015). Furthermore, the longer the pulse length, the
greater the thrombolysis efficiency, up to saturation
point. The saturation point was reached earlier when a shorter duty
cycle was used. For example, the use of a duty cycle of 1:10 allowed
for a continuous increase of pulse length and
thrombolysis efficiency up to saturation point at a
pulse length of 250 µs and thrombolysis efficiency of
90±1%. With a duty cycle of 1:40, saturation was reached at a pulse
length of 150 µs and thrombolysis efficiency of
45±2% (Figure 3).
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In choosing the optimal pulse length and duty cycle, several aspects
had to be considered: (1) a shorter duty cycle decreases the potential
tissue damage, whereas a longer duty cycle achieves greater
thrombolysis efficiency; (2) in shorter duty cycles,
thrombolysis efficiency can be enhanced by increasing
the Ispta; and (3) the use of a higher
Ispta can lead to migration of the cavitation
cloud outside the vessel (Figure 4).
Empirical experiments yielded the correct balance between the
variables: with a duty cycle of 1:25 and a pulse length of 200
µs, the cavitation cloud remained inside the vessel regardless of the
levels of Ispta.
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The relation between Ispta and
thrombolysis efficacy was studied by use of these
optimal PW parameters (Figure 5). At Ispta
<25±5 W/cm2, there was low
thrombolysis efficacy. At Ispta
>25±5 W/cm2, there was a steep increase in
thrombolysis efficiency. At Ispta
>35±5 W/cm2, an almost complete
thrombolysis was achieved.
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Ultrasound Imaging Observations
Ultrasound imaging of the thrombotic artery in the long-axis-view
preparation before sonication demonstrated the vessel walls and the
mild echo-dense thrombus occupying the vessel lumen (Figure 6). During sonication
(Ispta >35 W/cm2), the
cavitation was clearly visible as a spherical cloud of echo-dense
material. When the cavitation interacted with the clot, the clot was
typically shifted (5 mm) toward the cavitation area within 3
seconds. After sonication with optimal PW and
Ispta parameters (duty cycle 1:25,
pulse length 200 µs, and Ispta 40
W/cm2), the vessel lumen was echo-lucent and
there was no sonographic evidence of residual clot or damage to the
arterial wall within <2 minutes.
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Analysis of Thrombus Debris
After use of optimal PW and intensity parameters (duty
cycle 1:25, pulse length 200 µs, and Ispta 40
W/cm2), 93±1% of the lysed clots became
subcapillary in size (<8 µm) (Figure 7). Higher intensity levels did not
change the thrombus debris distribution profile.
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Histopathology Analysis
In vitro, the experiments with naked arterial segments
showed a structurally intact arterial wall regardless of
the sonication parameters. Elastic fiber variability, which
reflects the state of the vessel at harvesting, had proportions similar
to those of control segments (Figure 8).
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No arterial damage was observed, regardless of the
parameters, in the in vitro experiments using tissue
sections. Coagulative necrosis in the tissue was observed for the high
ultrasound dose (Figure 9) when the
sonication time was >120 seconds in Ispta of 90
W/cm2 and when it was >300 seconds in
Ispta of 45 W/cm2.
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Although the data suggested that damage score correlated with
sonication time (Figure 9
), only when ultrasound was applied for
>5 minutes in 1 spot was there tissue damage, evidenced as coagulation
necrosis, isolated to a well-demarcated lesion. The tissue immediately
adjacent to the lesion, including the tissue between the lesion and the
therapeutic transducer, was histologically normal.
In vivo, the arterial wall was structurally intact
regardless of intensity and time of exposure. The structure of lipid
and muscle cells was similar to that in the control segments. The
morphology of the skin was unchanged from the control (Figure 10).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The use of ultrasound for thrombolysis delivered either via a catheter or externally was studied in the past decade by several groups. The spectrum of acoustic energy can be separated into 2 major zones, ie, below or above the cavitation threshold.9 The former is the energy zone of ultrasound, used for enhancement of pharmacological thrombolysis (UPT). The latter is the zone of stand-alone ultrasound thrombolysis, as well as that for ultrasound surgery and ultrasound-assisted liposuction.
Ultrasound-Enhanced Pharmacological Thrombolysis
Kudo pioneered the use of external ultrasound to accelerate
pharmacological thrombolysis.10 He showed
that when used together with recombinant tissue plasminogen
activator (rtPA), ultrasound can accelerate
recanalization of thrombotically occluded arteries
in vivo. This observation was later confirmed by other investigators
using external ultrasound sources and catheter-based
systems.11 12 13 14 It is noteworthy that whereas Kudo used
ultrasound of relatively low frequencies (200 kHz), other investigators
used higher frequencies (1 to 2 MHz) with subcavitation intensity.
Suchkova and coworkers15 recently reemphasized the
advantage of lower-frequency ultrasound (40 kHz) to optimize UPT.
It has been proposed that the mechanism of UPT is ultrasound-increased transport and uptake of rtPA into the clot.16 17 Moreover, UPT was shown not to be thermal but rather associated with transient reversible structural changes of the fibrin matrix of the clot.16 17 18 19 Importantly, UPT is not rtPA-specific and was also observed to be effective with the other thrombolytic agents urokinase and streptokinase.20 21
Ultrasound Thrombolysis
UPT requires the presence of a thrombolytic agent
in a therapeutic dose. Thrombolytic agents have significant
limitations, including complications and high cost.22
Because of these limitations, attempts have been made to use ultrasound
for thrombolysis as stand-alone therapy, ie, without
adjunct use of pharmacological thrombolytic agents.
Experimentally, high-power, low-frequency ultrasound was found to
selectively lyse thrombi with a wide margin of safety. The ultrasound
intensity required to lyse thrombi is 1/20 of that required
to induce arterial wall damage.23 The
resistance of arteries to ultrasound-induced damage was also noted in
ultrasound surgery and ultrasound-assisted lipoplasty
experiences.24 25 Finally, the resistance of arteries to
ultrasound-induced damage was noted to diminish with increased
ultrasound intensity.26
We have studied catheter-based ultrasound thrombolysis. Our experience in acute myocardial infarction, acute coronary syndromes, and occluded saphenous vein grafts suggests that high-power, low-frequency ultrasound delivered in a catheter-based system can achieve effective and safe thrombolysis.1 2 Similarly encouraging results were reported by Hamm et al,27 who used a different catheter-based ultrasound delivery system to lyse clots in patients with acute myocardial infarction. The risk of distal embolization after ultrasound thrombolysis was extensively addressed. In vitro, Hartnell et al28 demonstrated that most of the debris, consisting of platelet and red blood cell aggregates, are of subcapillary size, an improvement that was not observed in thrombolytic- and PTCA-treated patients.29 30
We hypothesized that an external high-power, low-frequency
ultrasound source can focus the energy from a distance to a clot within
the body and achieve thrombolysis with no damage to
structures lying in the path of the ultrasound beam. In this study, we
investigated in vitro external HIFU thrombolysis using
500-kHz pulsed ultrasound guided by ultrasound imaging. The use of the
correct PW parameters was critical to the success of the
system operation: external therapeutic ultrasound was found to be very
efficient in inducing rapid thrombolysis with no damage
to the arteries or intervening tissue. There was no need for adjunct
pharmacological agents. The generated debris was mostly (93% of clot
mass) subcapillary in size. It has been proposed that the mechanism of
ultrasound thrombolysis is by nonselective disruption
of the thrombus fibrin matrix by the imploding
cavitations.8 23 31 We identified tissue damage when
higher intensity levels (45 W/cm2) were applied
only for a relatively long time (>5 minutes), guaranteeing a
potentially wide therapeutic index. Furthermore, the tissue damage was
limited to the focal point, with none occurring to the intervening
tissue.
When the optimal operating parameters are used, external ultrasound can generate and sustain a stable field of cavitation. The ability to better control the cavitation effect by a monochromatic ultrasound technique yields a very effective thrombolysis compared with the effect of shock waves, in which the transient cavitation effect bore only modest thrombolytic efficiency.8
Other investigators have attempted external ultrasound thrombolysis. Because they used nonfocused, nonpulsing systems and no visual guidance, they were limited in their ability to accurately deliver therapeutic levels of ultrasound. The limitation was circumnavigated elegantly by the use of echo-contrast material, which lowers the cavitation threshold.32 Nevertheless, thermal injury was a significant safety problem that had to be addressed by a tissue cooling system.33 34
Conclusions
The results of this study suggest that external HIFU
thrombolysis may be a safe and effective method to
induce thrombolysis. In addition, ultrasound therapy
can be guided by ultrasound imaging to identify and optimize the
acoustic window, aim the therapeutic ultrasound, ensure generation of
cavitation, and monitor therapy. More clinical work is needed to
further evaluate this method and define its clinical feasibility and
potential risks to intervening tissues whose acoustic properties are
different from those of soft tissue, eg, lung tissue in
coronary applications and skull for intracranial
applications.
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Acknowledgments |
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The authors thank Esther Eshkol for her editorial assistance.
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Footnotes |
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Dr Rosenschein is a consultant to and shareholder in Angiosonics, manufacturer of the instruments used in this study.
Received October 20, 1999; revision received February 14, 2000; accepted February 18, 2000.
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 T. Ishibashi, M. Akiyama, H. Onoue, T. Abe, and H. Furuhata Can Transcranial Ultrasonication Increase Recanalization Flow With Tissue Plasminogen Activator? Stroke, May 1, 2002; 33(5): 1399 - 1404. [Abstract] [Full Text] [PDF]
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