doi: 10.1161/01.STR.0000171075.55249.13
(Stroke. 2005;36:1356-a.)
© 2005 American Heart Association, Inc.
Letters to the Editor |
High-Frequency Transtemporal Sonothrombolysis
Department of Internal Medicine II, University of Vienna, Vienna, Austria.
To the Editor:
Clinical trials in the field of transcranial ultrasound thrombolysis used 2-MHz Doppler devices. Available in vitro and animal studies only used ultrasound frequencies in lower ranges. In this context the highest evaluated frequency was 1 MHz,1–4 which was less sufficient when compared with lower frequencies in the kHz range.1,2,5 In our study, ultrasound with a maximum acoustic intensity of 0.72 W/cm2 (Food and Drug Administration limit) was used. Clots were focused with B-mode, which was then switched off, and sonication was performed only with 1.8-MHz Doppler ultrasound. The goal was to evaluate if high-frequency ultrasound can lyse clots after temporal bone passage.
Under optimal insonation conditions, up to 10% of the original energy might affect the target. Whether this amount of energy is enough to initiate prothrombolytic processes around the clots surface or at the endothelium cannot finally be answered because our in vitro model cannot mimic endothelium functions and, second, ultrasound impact was analyzed under diffusion conditions.6 The study revealed that temporal bone attenuated the ultrasound beam significantly so that the thrombolytic effect was lost. According to our data, only 10% of the maximum output intensity hits the thrombus, which comes to an effective energy of 
0.07 W/cm2. Data concerning comparatively low levels of energy and their effects on thrombolysis are rare. Kimura et al7 showed a significant effect of continuous ultrasound with an intensity of 0.07 W/cm2 plus recombinant tissue plasminogen activator, but they used a lower frequency (300 kHz). Recently Basta et al specifically focused on this problem.8 They used continuous 2.5-MHz ultrasound with an effective acoustic intensity of 0.099 W/cm2. Thereby ultrasound thrombolysis (plus recombinant tissue plasminogen activator, aspirin, heparin) was only effective in clots of coronary artery disease patients when compared with healthy subjects. The authors speculate that this effect was likely caused by chronic use of aspirin and heparin in coronary artery disease patients. We therefore conclude that the effect of high-frequency ultrasound under conditions mimicking reduced flow or constant pressure remains to be evaluated. Apart from this area of vagueness, a major influence of 2-MHz transcranial ultrasound on thrombolysis seems to be questionable, which is supported by clinical findings and cited in vitro studies.
Another study goal was to prove if ultrasound impact can be simply calculated without the effort of studies. We found that calculations implementing ultrasound parameters and tissue barriers were comparable to experimental findings. This suggests that further studies in this field might benefit from extensive calculations. The still remaining key question about crucial ultrasound parameters and their effects on human tissues therefore might be clarified before studies or might at least enable a more efficient selection. However, many biological parameters or tissue-specific constants are not available and deserve attention. For example, what effect is exerted by continuous diagnostic Doppler sonication on human brain tissue when applied over 1 hour? Can negative side effects really be excluded? More basic studies in this field are essential to adapt ultrasound parameters properly. If sonication with ultrasound frequencies lower than 2 MHz might exert the desired impact on thrombolysis remains to be investigated.
References
1. Akiyama M, Ishibashi T, Yamada T, Furuhata H. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Neurosurgery. 1998; 43: 828–833.[CrossRef][Medline] [Order article via Infotrieve]
2. Behrens S, Spengos K, Daffertshofer M, Schroeck H, Dempfle CE, Hennerici M. Transcranial ultrasound-improved thrombolysis: diagnostic vs. therapeutic ultrasound. Ultrasound Med Biol. 2001; 27: 1683–1689.[CrossRef][Medline] [Order article via Infotrieve]
3. Culp WC, Erdem E, Roberson PK, Husain MM. Microbubble potentiated ultrasound as a method of stroke therapy in a pig model: preliminary findings. J Vast Interv Radiol. 2003; 14: 1433–6.
4. Hardig BM, Persson HW, Gido G, Olsson SB. Does low-energy ultrasound, known to enhance thrombolysis, affect the size of ischemic brain damage? J Ultrasound Med. 2003; 22: 1301–1308.
5. Behrens S, Daffertshofer M, Spiegel D, Hennerici M. Low-frequency, low-intensity ultrasound accelerates thrombolysis through the skull. Ultrasound Med Biol. 1999; 25: 269–273.[CrossRef][Medline] [Order article via Infotrieve]
6. Pfaffenberger S, Devcic-Kuhar B, Kollmann C, Kastl SP, Kaun C, Speidl WS, Weiss TW, Demyanets S, Ullrich R, Sochor H, Wober C, Zeitlhofer J, Huber K, Groschl M, Benes E, Maurer G, Wojta J, Gottsauner-Wolf M. Can a commercial diagnostic ultrasound device accelerate thrombolysis? An in vitro skull model. Stroke. 2005; 36: 124–128.
7. Kimura M, Iijima S, Kobayashi K, Furuhata H. Evaluation of the thrombolytic effect of tissue-type plasminogen activator with ultrasonic irradiation: in vitro experiment involving assay of the fibrin degradation products from the clot. Biol Pharm Bull. 1994; 17: 126–130.[Medline] [Order article via Infotrieve]
8. Basta G, Lupi C, Lazzerini G, Chiarelli P, L’Abbate A, Rovai D. Therapeutic effect of diagnostic ultrasound on enzymatic thrombolysis. An in vitro study on blood of normal subjects and patients with coronary artery disease. Thromb Haemost. 2004; 91: 1078–1083.[Medline] [Order article via Infotrieve]
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