The effect of ultrasound on the rate of fibrinolysis has been investigated using an in vitro system. Plasma or blood clots containing a trace label of 125I fibrin were suspended in plasma containing plasminogen activator and intermittently exposed to continuous wave 1-MHz ultrasound at intensities up to 8 W/ cm2. Plasma clot lysis at 1 h with 1 igg/ml recombinant tissue plasminogen activator (rt-PA) was 12.8±1.2% without ultrasound and was significantly (P = 0.0001) increased by exposure to ultrasound with greater lysis at 1 W/cm2 (18.0 ± 1.4%), 2 W/cm2 (19.3 ± 0.7%), 4 W/cm2 (22.8 ± 1.8%), and 8 W/cm2 (58.7 ± 7.1%). Significant increases in lysis were also seen with urokinase at ultrasound intensities of 2 W/cm2 and above. Exposure of clots to ultrasound in the absence of plasminogen activator did not increase lysis. Ultrasound exposure resulted in a marked reduction in the rt-PA concentration required to achieve an equivalent degree of lysis to that seen without ultrasound. For example, 15% lysis occurred in 1 h at 1 gg/ml rt-PA without ultrasound or with 0.2 ug/ml with ultrasound, a fivefold reduction in concentration. Ultrasound at 1 W/cm2 and above also potentiated lysis of retracted whole blood clots mediated by rt-PA or urokinase. The maximum temperature increase of plasma clots exposed to 4 W/cm2 ultrasound was only 1.7°C, which could not explain the enhancement offibrinolysis. Ultrasound exposure did not cause mechanical fragmentation of the clot into sedimentable fragments, nor did it alter the sizes of plasmic derivatives as demonstrated by SDS polyacrylamide gel electrophoresis. We conclude that ultrasound at 1 MHz potentiates enzymatic fibrinolysis by a nonthermal mechanism at energies that can potentially be applied and tolerated in vivo to accelerate therapeutic fibrinolysis. (J.

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Background-Ultrasound at frequencies of 0.5 to 1 MHz and intensities of Ն0.5 W/cm 2 accelerates enzymatic fibrinolysis in vitro and in some animal models, but unacceptable tissue heating can occur, and limited penetration would restrict application to superficial vessels. Tissue heating is less and penetration better at lower frequencies, but little information is available regarding the effect of lower-frequency ultrasound on enzymatic fibrinolysis. We therefore examined the effect of 40-kHz ultrasound on fibrinolysis, tissue penetration, and heating. Methods and Results-125 I-fibrin-radiolabeled plasma clots in thin-walled tubes were overlaid with plasma containing tissue plasminogen activator (tPA) and exposed to ultrasound. Enzymatic fibrinolysis was measured as solubilization of radiolabel. Tissue attenuation and heating were examined in samples of porcine rib cage. Fibrinolysis was increased significantly in the presence of 40-kHz ultrasound at 0.25 W/cm 2 , reaching 39Ϯ7% and 93Ϯ11% at 60 minutes and 120 minutes, compared with 13Ϯ8% and 37Ϯ4% in the absence of ultrasound (PϽ0.0001). The acceleration of fibrinolysis increased at higher intensities. Attenuation of the ultrasound field was only 1.7Ϯ0.5 dB/cm through the intercostal space and 3.4Ϯ0.9 dB/cm through rib. Temperature increments in rib were Ͻ1°C/(W/cm 2 ). Conclusions-These findings indicate that 40-kHz ultrasound significantly accelerates enzymatic fibrinolysis at intensities of Ն0.25 W/cm 2 with excellent tissue penetration and minimal heating. Externally applied 40-kHz ultrasound at low intensities is a potentially useful therapeutic adjunct to enzymatic fibrinolysis with sufficient tissue penetration for both peripheral vascular and coronary applications.

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This review examines the nonthermal physical mechanisms by which ultrasound can harm tissue in postnatal patients. First the physical nature of the more significant interactions between ultrasound and tissue is described, followed by an examination of the existing literature with particular emphasis on the pressure thresholds for potential adverse effects. The interaction of ultrasonic fields with tissue depends in a fundamental way on whether the tissue naturally contains undissolved gas under normal physiologic conditions. Examples of gas-containing tissues are lung and intestine. Considerable effort has been devoted to investigating the acoustic parameters relevant to the threshold and extent of lung hemorrhage. Thresholds as low as 0.4 MPa at 1 MHz have been reported. The situation for intestinal damage is similar, although the threshold appears to be somewhat higher. For other tissues, auditory stimulation or tactile perception may occur, if rarely, during exposure to diagnostic ultrasound; ultrasound at similar or lower intensities is used therapeutically to accelerate the healing of bone fractures. At the exposure levels used in diagnostic ultrasound, there is no consistent evidence for adverse effects in tissues that are not known to contain stabilized gas bodies. Although modest tissue damage may occur in certain identifiable applications, the risk for induction of an adverse biological effect by a nonthermal mechanism due to exposure to diagnostic ultrasound is extremely small.