Sonothrombolysis: Experimental evidence
Sonothrombolysis: Experimental evidence
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DOI：
10.1159/000092396
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
Hennerici, Michael
中科院分区：
文献类型：
--
作者：
Daffertshofer, Michael;Hennerici, Michael
重新开放闭塞动脉是超急性缺血性中风的主要治疗目标。组织重组纤溶酶原激活剂 (tPA) 的全身治疗已被证明至少在 3 小时门到针窗口内是有益的。动脉内溶栓是有利的，并且可以打开至少6小时的治疗窗口，但会导致大量患者进行侵入性动脉内血管造影，其中相当一部分患者最终没有接受溶栓治疗。超声与溶栓剂的结合可以通过酶介导的溶栓来增强潜在的益处。当超声波通过皮肤或胸部从外部施加时，衰减会非常低。然而，如果需要穿透颅骨，衰减会明显更高。衰减与频率相关，超声强度 < 诊断频率 (> 1MHz) 输出强度的 10%。该比率在千赫兹范围内 (< 500 kHz) 几乎相反。超声波在各种强度范围内（从 0.5 W/cm² (MI~ 0.3) 到每平方厘米数瓦特）可有效加速酶溶血栓，特别是在非聚焦超声波领域。在静态模型中，超声波使 tPA 介导的血栓溶解增加高达 20%，而在流动模型中，则将再通率从 30% 提高到 90%。栓塞大鼠模型的结果表明，与纯 tPA 治疗相比，0.6 W/cm² 低频超声可显着减少梗塞体积。用于治疗目的的大脑超声暴露的安全性必须解决出血、发热和直接组织损伤的问题。由于动物研究表明出血率不会增加或对血脑屏障造成损害，因此一项应用约 300kHz 低频超声的临床 II 期研究发现大量继发性出血。加热主要取决于超声波的特性。使用 2 W/cm² 探头时，脑组织本身最显着的加热是每小时 > 1 C；然而，当使用脉冲超声波的发射协议时，没有发现明显的加热。目前的实验数据有助于确定声波溶栓的最佳超声特征，并支持联合治疗是优化急性中风溶栓治疗观点的假设。
Reopening of the occluded artery is the primary therapeutic goal in hyperacute ischemic stroke. Systemic treatment with tissue recombinant plasminogen activator (tPA) has been shown to be beneficial at least in a 3-hour door to needle window. Intra-arterial throm-bolysis is favorable and opens the window of treatment up to at least 6h but consequences invasive intra-arterial angiography in a high number of patients, of whom a significant num-ber do not finally receive thrombolysis. The combination of ultrasound with thrombolytic agents may enhance the potential benefit by means of enzyme-mediated thrombolysis. When ultrasound is applied externally through skin or chest, attenuation will be very low. Attenuation, however, is significantly higher if penetration through the skull is required. Attenuation is frequency dependent, with ultrasound intensity being< 10% of the output intensity for diagnostic frequencies (> 1MHz). This ratio nearly reverses in the kiloHertz range (< 500 kHz). Ultrasound insonation is efficient for accelerating enzymatic thromboly-sis within a wide range of intensities, from 0.5 W/cm² (MI~ 0.3) to several watts per square centimeter, particularly in the nonfocused ultrasound field. Insonation with ultrasound increased tPA-mediated thrombolysis up to 20% in a static model, while it enhanced the recanalization rate from 30 to 90% in a flow model. Results from embolic rat models suggest that low-frequency ultrasound with 0.6 W/cm² significantly reduces infarct volume com-pared to pure tPA treatment. Safety of ultrasound exposure of the brain for therapeutic pur-poses has to address hemorrhage, heating, and direct tissue damage. Since animal studies suggested no increase of bleeding rate or harm to the blood-brain barrier, a clinical phase II study applying low-frequency ultrasound at~ 300kHz found a high number of secondary hemorrhages. Heating depends critically on the characteristics of the ultrasound. The most significant heating of the brain tissue itself is> 1 C per hour using a 2 W/cm² probe; however, no significant heating could be found when using an emission protocol pulsing the ultrasound. The current experimental data helps to identify the optimal ultrasound characteristics for sonothrombolysis and supports the hypothesis combined treatment being a perspeс-tive in optimizing thrombolytic therapy in acute stroke.