Ultrasound Energy and the Dissolution of Thrombus
http://www.100md.com
《新英格兰医药杂志》
In this issue of the Journal, Alexandrov et al. (pages 2170–2178) introduce practicing physicians to a new and exciting use of diagnostic ultrasonography. The authors show that ultrasound energy, used in combination with tissue plasminogen activator (t-PA), has a beneficial effect in patients with acute ischemic stroke. The type of stroke treated by the authors is due primarily to thromboembolism, and the source of the thrombus is often the carotid bifurcation, although the heart and even the ascending aorta and proximal aortic arch can serve as sources of embolic material. The results of prospective randomized trials, summarized in a meta-analysis by Hacke et al.,1 confirm that administering a thrombolytic agent in a patient with evolving stroke can be beneficial. However, in order for there to be long-lasting benefits, the agent must be administered within three hours after the onset of symptoms. Is it possible to accelerate the dissolution of these emboli and potentially increase the duration of this critical window?
During the past 30 years, investigators have studied various approaches to harnessing ultrasound energy for the purpose of recanalizing occluded vessels. The first approach involved a specially designed catheter, a prototype of which was used in the early 1970s. Since then, catheter-based methods have become more sophisticated. By a process called cavitation, these devices can clear arteries of acute thrombus without damaging the arterial wall. Ultrasound of sufficient amplitude, when applied to a fluid, causes the partly dissolved gases to form small bubbles. These bubbles then vibrate, absorbing the energy, and if enough energy is applied, they literally explode. Invasive catheters and some transcutaneous devices generate enough ultrasound energy to cause cavitation — an amount of energy similar to that used in a therapeutic laser. At the same power levels, it is much harder to cause tissue damage with ultrasound than with a laser.
However, this mechanism is unlikely to be responsible for the effect observed in the study by Alexandrov et al., because transcutaneous ultrasound devices are preset to prevent excessive deposition of ultrasound energy. Still, it is theoretically possible, although it is unlikely, that some gaseous bubbles trapped in the thrombus may be the right size and composition to meet the threshold for the onset of cavitation. The local effect would be to create gaps or symmetric "holes" in the fibrin mesh, thereby facilitating the permeation of t-PA into the thrombus (see Figure).
Figure. Mechanism of Action of Tissue Plasminogen Activator (t-PA) and Possible Mechanisms of Action of Ultrasound Energy in the Dissolution of Thrombus.
Other effects depend on the level of ultrasound energy applied. At very low energies, ultrasound has been shown to promote the motion of fluid, an effect called microstreaming. It is possible that the application of ultrasound energy agitates the blood close to the occluding thrombus and promotes the mixing of t-PA, effectively increasing the concentration of the agent that is in contact with the thrombus. The pressure waves that are generated may also increase the permeation of t-PA into the interior of the fibrin network. This phenomenon, however, is unlikely to explain all the beneficial results observed in this study. At slightly higher energies, ultrasound waves can have direct effects on the binding of t-PA to the fibrin mesh that forms the occlusive lesion. The binding of t-PA to the cross-linked fibrin and fibrin elements within a matrix is enhanced, in vitro, by ultrasound energy,2 and the fibrin cross-links are weakened, further increasing the binding of t-PA. These two mechanisms probably play key roles in vivo.
Some authors have speculated that the heat generated by ultrasound is responsible for accelerating thrombolysis. Experiments have confirmed that the temperature elevation generated by ultrasound of sufficient power can increase the dissolution rate of thrombi. Ultrasound energy causes some amount of temperature elevation in the body. In diagnostic ultrasound devices, the amount of energy delivered by the imaging transducer is closely monitored, and there are standards regarding acceptable increases in temperature. Could this still be the mechanism primarily responsible for the observations of Alexandrov et al.? It is possible but not likely. A major limitation of transcranial ultrasonography is attenuation of ultrasound waves by the bones of the cranium. This is why transcranial Doppler sonography relies on the use of imaging windows in areas where the bone of the cranium is thin. Even with the existence of these windows, diagnostic imaging and the therapeutic use of ultrasound may not be possible in 10 to 15 percent of patients. At the temporal-bone window, the ultrasound beam must still traverse a substantial amount of bone. In doing so, the beam becomes attenuated, and energy is deposited in the bone and transmitted to the surrounding soft tissues. Thus, this is where heating is likely to occur — at a site far from where a therapeutic effect is desired.
In summary, the mechanism responsible for the effect of ultrasound on thrombus dissolution is not completely known. Still, its acceleration of thrombolysis makes biologic sense, and it works clinically. There is reason to be optimistic that future technological improvements will lead to even better efficacy.
Dr. Polak reports having served as a consultant to Omnisonics.
Source Information
From the Department of Radiology, New England Medical Center and Tufts School of Medicine, Boston.
References
Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774.
Sakharov DV, Barrertt-Bergshoeff M, Hekkenberg RT, Rijken DC. Fibrin-specificity of a plasminogen activator affects the efficiency of fibrinolysis and responsiveness to ultrasound: comparison of nine plasminogen activators in vitro. Thromb Haemost 1999;81:605-612.(Joseph F. Polak, M.D., M.)
During the past 30 years, investigators have studied various approaches to harnessing ultrasound energy for the purpose of recanalizing occluded vessels. The first approach involved a specially designed catheter, a prototype of which was used in the early 1970s. Since then, catheter-based methods have become more sophisticated. By a process called cavitation, these devices can clear arteries of acute thrombus without damaging the arterial wall. Ultrasound of sufficient amplitude, when applied to a fluid, causes the partly dissolved gases to form small bubbles. These bubbles then vibrate, absorbing the energy, and if enough energy is applied, they literally explode. Invasive catheters and some transcutaneous devices generate enough ultrasound energy to cause cavitation — an amount of energy similar to that used in a therapeutic laser. At the same power levels, it is much harder to cause tissue damage with ultrasound than with a laser.
However, this mechanism is unlikely to be responsible for the effect observed in the study by Alexandrov et al., because transcutaneous ultrasound devices are preset to prevent excessive deposition of ultrasound energy. Still, it is theoretically possible, although it is unlikely, that some gaseous bubbles trapped in the thrombus may be the right size and composition to meet the threshold for the onset of cavitation. The local effect would be to create gaps or symmetric "holes" in the fibrin mesh, thereby facilitating the permeation of t-PA into the thrombus (see Figure).
Figure. Mechanism of Action of Tissue Plasminogen Activator (t-PA) and Possible Mechanisms of Action of Ultrasound Energy in the Dissolution of Thrombus.
Other effects depend on the level of ultrasound energy applied. At very low energies, ultrasound has been shown to promote the motion of fluid, an effect called microstreaming. It is possible that the application of ultrasound energy agitates the blood close to the occluding thrombus and promotes the mixing of t-PA, effectively increasing the concentration of the agent that is in contact with the thrombus. The pressure waves that are generated may also increase the permeation of t-PA into the interior of the fibrin network. This phenomenon, however, is unlikely to explain all the beneficial results observed in this study. At slightly higher energies, ultrasound waves can have direct effects on the binding of t-PA to the fibrin mesh that forms the occlusive lesion. The binding of t-PA to the cross-linked fibrin and fibrin elements within a matrix is enhanced, in vitro, by ultrasound energy,2 and the fibrin cross-links are weakened, further increasing the binding of t-PA. These two mechanisms probably play key roles in vivo.
Some authors have speculated that the heat generated by ultrasound is responsible for accelerating thrombolysis. Experiments have confirmed that the temperature elevation generated by ultrasound of sufficient power can increase the dissolution rate of thrombi. Ultrasound energy causes some amount of temperature elevation in the body. In diagnostic ultrasound devices, the amount of energy delivered by the imaging transducer is closely monitored, and there are standards regarding acceptable increases in temperature. Could this still be the mechanism primarily responsible for the observations of Alexandrov et al.? It is possible but not likely. A major limitation of transcranial ultrasonography is attenuation of ultrasound waves by the bones of the cranium. This is why transcranial Doppler sonography relies on the use of imaging windows in areas where the bone of the cranium is thin. Even with the existence of these windows, diagnostic imaging and the therapeutic use of ultrasound may not be possible in 10 to 15 percent of patients. At the temporal-bone window, the ultrasound beam must still traverse a substantial amount of bone. In doing so, the beam becomes attenuated, and energy is deposited in the bone and transmitted to the surrounding soft tissues. Thus, this is where heating is likely to occur — at a site far from where a therapeutic effect is desired.
In summary, the mechanism responsible for the effect of ultrasound on thrombus dissolution is not completely known. Still, its acceleration of thrombolysis makes biologic sense, and it works clinically. There is reason to be optimistic that future technological improvements will lead to even better efficacy.
Dr. Polak reports having served as a consultant to Omnisonics.
Source Information
From the Department of Radiology, New England Medical Center and Tufts School of Medicine, Boston.
References
Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774.
Sakharov DV, Barrertt-Bergshoeff M, Hekkenberg RT, Rijken DC. Fibrin-specificity of a plasminogen activator affects the efficiency of fibrinolysis and responsiveness to ultrasound: comparison of nine plasminogen activators in vitro. Thromb Haemost 1999;81:605-612.(Joseph F. Polak, M.D., M.)