Daffertshofer Michael, Hennerici Michael G
Department of Neurology, University of Heidelberg, University Hospital Mannheim, Mannheim, Germany.
Front Neurol Neurosci. 2006;21:140-149. doi: 10.1159/000092396.
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 thrombolysis is favorable and opens the window of treatment up to at least 6 h but consequences invasive intra-arterial angiography in a high number of patients, of whom a significant number 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 (>1 MHz). This ratio nearly reverses in the kiloHertz range (>500 kHz). Ultrasound insonation is efficient for accelerating enzymatic thrombolysis within a wide range of intensities, from 0.5W/cm2 (MI approximately 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 0.6W/cm2 significantly reduces infarct volume compared to pure tPA treatment. Safety of ultrasound exposure of the brain for therapeutic purposes 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 approximately 300 kHz 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 degrees C per hour using a 2W/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 perspective in optimizing thrombolytic therapy in acute stroke.
开通闭塞动脉是超急性缺血性卒中的主要治疗目标。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小时的门到针时间窗内是有益的。动脉内溶栓是有利的，并且将治疗时间窗延长至至少6小时，但会对大量患者进行有创动脉血管造影，其中相当数量的患者最终未接受溶栓治疗。超声与溶栓药物联合使用可能通过酶介导的溶栓作用增强潜在益处。当超声通过皮肤或胸部进行外部应用时，衰减将非常低。然而，如果需要穿透颅骨，衰减会显著更高。衰减与频率相关，对于诊断频率（>1MHz），超声强度小于输出强度的10%。在千赫兹范围内（>500kHz），这个比例几乎相反。超声照射在从0.5W/cm²（MI约为0.3）到每平方厘米几瓦的广泛强度范围内，对于加速酶促溶栓是有效的，特别是在非聚焦超声场中。在静态模型中，超声照射使tPA介导的溶栓增加高达20%，而在血流模型中，它将再通率从30%提高到90%。栓塞大鼠模型的结果表明，与单纯tPA治疗相比，0.6W/cm²的低频超声显著减少梗死体积。用于治疗目的的脑部超声暴露的安全性必须考虑出血、发热和直接组织损伤。由于动物研究表明出血率没有增加，对血脑屏障也没有损害，一项应用约300kHz低频超声的临床II期研究发现了大量继发性出血。发热严重依赖于超声的特性。使用2W/cm²探头时，脑组织本身最显著的发热是每小时>1℃；然而，当使用超声脉冲发射方案时，未发现明显发热。目前的实验数据有助于确定超声溶栓的最佳超声特性，并支持联合治疗是优化急性卒中溶栓治疗的一个前景的假设。
