摘要
为了提高超声溶栓治疗的安全性、有效性,我们设计了一种治疗与诊断双模式超声溶栓(DMUT)系统。其空间峰值时间平均功率(ISPTA)只有FDA规定的1/3,机械指数(MI)只有最大允许值的1/6,且治疗声束在空间及时间上都受到限制,以避免颅内驻波的形成及其可能危害。离体流路模型实验证实该系统可以明显增强tPA的溶栓作用,且可以提供多普勒诊断信息,以方便低频治疗超声的定位、并监测血管再开通过程的变化。
此外,为了更加精确、高效地研究超声的溶栓增强作用,我们还设计了一种新的光学超声溶栓定量评价法。该方法利用照相技术,通过检查相片局部光亮度的变化,确定血栓厚度的变化,操作较简单,对血栓的人为影响小,具有良好的可重复性,同时可以区分不同声场位置处血栓厚度的变化。利用该方法,我们成功地证实:在离体条件下,普通经颅多普勒(TCD)超声诊断系统也有显著的溶栓促进作用。这既为临床应用TCD促进血栓溶解找到了部分依据,也显示了该实验方法具有很高的灵敏度。
To improve the safety and efficiency of ultrasonic thrombolysis, we designed a dual mode ultrasonic thrombolysis (DMUT) system. Its spatial peak temporal average intensity was only 1/3 of that of the up-limit cleared by FDA, and its mechanic index was only 1/6 that of the cleared limit. It was also spatially and temporally restricted to avoid the forming of standing waves. Its effect in enhancement of TPA thrombolysis was confirmed by experiments with an in vitro flow model, and its ability to provide Doppler information of the blood flow, which can be used to aiming the therapeutic ultrasound beam and monitoring the recanalization process, was also demonstrated.
Further, we also designed a new optical quantitative evaluation method for ultrasonic thrombolysis. It made use of photography to determine the thickness of clot by examining the photo brightness. With relatively simple operation and less personal interference, it had a rather good reproducibility, and could differentiate the thickness changes of different parts of the sound field. By this method we successfully demonstrated that a common TCD diagnostic system have the ability to enhance the thrombolysis significantly, thus provided the support for the clinical use of TCD for such objectives and showed the high sensitivity of this method.
引文
1. del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, Alberts MJ, Zivin JA, Wechsler L, Busse O. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992;32:78–86.
2. Brott TG, Haley EC, Levy DE, Barsan W, Broderick J, Sheppard GL, Spilker J, Kongable GL, Massey S, Reed R. Urgent therapy for stroke. Part I. pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992;23:632– 640.
3. Haley EC, Levy DE, Brott TG, Sheppard GL, Wong MC, Kongable GL, Torner JC, Marler JR. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91–180 minutes from onset. Stroke 1992;23:641– 645.
4. The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–1587.
5. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke: the European Cooperative Acute Stroke Study. JAMA 1995;274:1017–1025.
6. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II): Second European–Australasian Acute Stroke Study Investigators. Lancet 1998;352:1245–1251.
7. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768 –774.
8. Haley EC, Lewandowski C, Tilley BC. Myths regarding NINDS rt-PA stroke trial: setting the record straight. Ann Emerg Med 1997;30:676–682.
9. Demchuk AM, Felberg RA, Alexandrov AV. Clinical recovery from acute ischemic stroke after early reperfusion of the brain with intravenous thrombolysis. N Engl J Med 1999;340:894–895.
10. Grotta JC, Alexandrov AV. TPA-associated reperfusion in acute ischemic stroke demonstrated by SPECT. Stroke 1998:29:429–432.
11. Heiss W-D, Grond M, Thiel A, von Stockhausen HM, Rudolf J, Ghaemi M, Lottgen J, Stenzel C, Pawlik G. Tissue at risk of infarction rescued by early reperfusion: a positron emission tomography study in systemic recombinant tissue plasminogen activator thrombolysis of acute stroke. J Cereb Blood Flow Metab 1998;18:1298–1307.
12. Ringelstein EB, Biniek R, Weiller C, Ammeling B, Nolte PN, Thron A. Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization. Neurology 1992;42:289 –298. 13. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007;38:967–973.
14. Trubestein R, Bernard HR, Etzel F, Sobbe A, Cremer A, Stumpff U. Thrombolysis by ultrasound. Clin Sci Mol Med 1976;51:697–698.
15. Tachibana K, Tachibana S. Ultrasonic vibration for boosting fibrinolytic effects of urokinase in vivo [abstract]. Thromb Haemost 1981;46:211.
16. Lauer CG, Burge R, Tang DB, Bass BG, Gomez ER, Alving BM. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation 1992;86:1257–1264.
17. Kimura M, Iijima S, Kobayashi K, Furuhata H. Evaluation of the thrombolytic effect of tissue-type plasminogen activator with ultrasound irradiation: in vitro experiment involving assay of the fibrin degradation products from the clot. Biol Pharm Bull 1994;17:126 –130.
18. Akiyama M, Ishibashi T, Yamada T, Furuhata H. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Neurosurgery 1998;43:828–832.
19. Suchkova V, Siddiqi FN, Carstensen EL, Dalecki D, Child S, Francis CW. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998;98:1030 –1035.
20. 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.
21. Polak JF. Ultrasound energy and the dissolution of thrombus. N Engl J Med 2004;351:2154 –2155.
22. 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.
23. Spengos K, Behrens S, Daffertshofer M, Dempfle CE, Hennerici M. Acceleration of thrombolysis with ultrasound through the cranium in a flow model. Ultrasound Med Biol 2000;26:889–895.
24. 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.
25. Blinc A, Francis CW, Trudnowski JL, Carstensen EL. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood 1993; 81:2636 –2643.
26. Alexandrov AV, Demchuk AM, Felberg RA, Christou I, Barber PA, Burgin WS, Malkoff M, Wojner AW, Grotta JC. High rate of complete recanalization and dramatic clinical recovery during TPA infusion when continuously monitored by 2-MHz transcranial Doppler monitoring. Stroke 2000:31:610–614.
27. Chernyshev OY, Garami Z, Calleja S, Song J, Campbell MS, Noser EA, Shaltoni H, Chen CI, Iguchi Y, Grotta JC, Alexandrov AV. The yield and accuracy of urgent combined carotid-transcranial ultrasound testing in acute cerebral ischemia. Stroke 2005;36:32–37.
28. Tsivgoulis G, Sharma VK, Lao AY, Malkoff MD, Alexandrov AV. Validation of transcranial Doppler with computed tomography angiography in acute cerebral ischemia. Stroke 2007;38:1245–1249.
29. Kim YS, Meyer JS, Garami Z, Molina CA, Pavlovic AM, Alexandrov AV. Flow diversion in transcranial Doppler ultrasound is associated with better improvement in patients with acute middle cerebral artery occlusion. Cerebrovasc Dis 2006;21:74 –78.
30. Kim YS, Garami Z, Mikulik R, Molina CA, Alexandrov AV; CLOTBUST Collaborators. Early recanalization rates and clinical outcomes in patients with tandem internal carotid artery/middle cerebral artery occlusion and isolated middle cerebral artery occlusion. Stroke 2005;36:869–871.
31. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004;351:2170 –2178.
32. Eggers J, Koch B, Meyer K, Konig I, Seidel G. Effect of ultrasound on thrombolysis of middle cerebral artery occlusion. Ann Neurol 2003;53:797– 800.
33. Eggers J, Seidel G, Koch B, Konig IR. Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA. Neurology 2005; 64:1052–1054.
34. Cintas P, Le Traon AP, Larrue V. High rate of recanalization of middle cerebral artery occlusion during 2-MHz transcranial color coded Doppler continuous monitoring without thrombolytic drug. Stroke 2002;33:626–628.
35. Skoloudik D, Bar M, Hradilek P, Vaclavik D, Skoda O. Safety and efficacy of thrombotripsy: acceleration of thrombolysis by TCCS. In: Proceedings ofthe NSRG 2003 Meeting, Germany: Karger [CD-ROM].
36. Mahon BR, Nesbit GM, Barnwell SL, Clark W, Marotta TR, Weill A, Teal PA, Qureshi AI. North American clinical experience with the EKOS MicroLysUS infusion catheter for treatment of embolic stroke[J]. AJNR Am J Neuroradiol 2003,24:534-538
37. The IMS Study Investigators. Combined intravenous and intraarterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke 2004;35:904 –912.
38. Daffertshofer M, Hennerici M. Ultrasound in the treatment of ischaemic stroke. Lancet Neurol 2003;2:283–290.
39. Behrens S, Spengos K, Daffertshofer M, Wirth S, Hennerici M. Potential use of therapeutic ultrasound in ischemic stroke treatment. Echocardiography 2001;18:259 –263.
40. Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, Sedlaczek O, Koroshetz WJ, Hennerici MG. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator. Stroke 2005;36:1441–1446.
41. Reinhard M, Hetzel A, Kruger S, Kretzer S, Talazko J, Ziyeh S, Weber J, Els T. Blood-brain barrier disruption by low-frequency ultrasound. Stroke 2006;37:1546 –1548.
42. Schneider F, Gerriets T, Walberer M, Mueller C, Rolke R, Eicke BM, Bohl J, Kempski O, Kaps M, Bachmann G, Dieterich M, Nedelmann M. Brain edema and intracerebral necrosis caused by transcranial low-frequency20-kHz ultrasound: A safety study in rats. Stroke 2006;37:1301–1306.
43. Azuma T, Kawabata K, Umemura S, Ogihara M, Kubota J, Sasaki A, Furuhata H. Bubble generation by standing wave in water surrounded by cranium with transcranial ultrasonic beam. Jpn J Appl Phys 2005;44:625– 630.
44. Unger EC, Porter T, Culp W, Labell R, Matsunaga T, Zutshi R. Therapeutic applications of lipid-coated microbubbles. Adv Drug Deliv Rev 2004;56:1291–1314.
45. Culp WC, Porter TR, McCowan TC, Roberson PK, James CA, Matchett WJ, Moursi M. Microbubble-augmented ultrasound declotting of thrombosed arteriovenous dialysis grafts in dogs. J Vasc Interv Radiol 2003;14:343–347.
46. Culp WC, Porter TR, Lowery J, Xie F, Roberson PK, Marky L. Intracranial clot lysis with intravenous microbubbles and transcranial ultrasound in swine. Stroke 2004;35:2407–2411.
47. Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, Arenillas JF, Huertas R, Purroy F, Delgado P, Alvarez-Sabin J. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006;37:425–429.
48. Alexandrov AV, Mikulik R, Ribo M, Sharma VK, Lao AY, Tsivgoulis G, Sugg RM, Barreto A, Sierzenski P, Malkoff MD, Grotta JC. A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke.Stroke. 2008 May;39(5):1464-9.
49. Perren F, Loulidi J, Poglia D, Landis T, Sztajzel R. Microbubble potentiated transcranial duplex ultrasound enhances IV thrombolysis in acute stroke. J Thromb Thrombolysis. May 20, 2007 [Epub ahead of print].
50. Larrue V, Viguier A, Arnaud C, et al. Transcranial ultrasound combined with intravenous microbubbles and tissue plasminogen activator for acute ischemic stroke: a randomized controlled study [abstract]. Stroke 2007;38:472.
51. Sharma VK, Tsivgoulis G, Lao AY, Malkoff MD, Alexandrov AW, Alexandrov AV. Quantification of microbubble appearance in brain vessels: implications for dose calculations and drug delivery [abstract]. Stroke 2007;38:493.
52. The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997; 28:2109 –2118.
53. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study investigators. Lancet 1998;352:1245–1251.
54. Daffertshofer M, Huang Z, Fatar M, Popolo M, Schroeck H, Kuschinsky W, Moskowitz MA, Hennerici MG. Efficacy of sonothrombolysis in a rat model of embolic ischemic stroke. Neurosci Lett 2004;361:115–119.
55. Ishibashi T, Akiyama M, Onoue H, Abe T, Furuhata H. Can transcranial ultrasonication increase recanalization flow with tissue plasminogenactivator? Stroke 2002;33:1399 –1404.
56. FDA. Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers. Center for Devices and Radiological Health, Food & Drug Administration, 9200 Corporate Blvd, Rockville MD 20850, 1997.
57. Suchkova VN, Baggs RB, Francis CW. Effect of 40-kHz ultrasound on acute thrombotic ischemia in a rabbit femoral artery thrombosis model: Enhancement of thrombolysis and improvement in capillary muscle perfusion. Circulation 2000;101:2296 –2301.
58. Blinc A, Kennedy SD, Bryant RG, Marder VJ, Francis CW. Flow through clots determines the rate and pattern of fibrinolysis. Thromb Haemost 1994;71:230 –235.