Therapeutic application of contrast-enhanced ultrasound and low-dose urokinase for thrombolysis in a porcine model of acute peripheral arterial occlusion
Therapeutic application of contrast-enhanced ultrasound and low-dose urokinase for thrombolysis in a porcine model of acute peripheral arterial occlusion
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DOI：
10.1016/j.jvs.2014.02.057
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发表时间：
2015-08-01
影响因子：
4.3
通讯作者：
Yeung, Kak K.
中科院分区：
文献类型：
--
作者：
Ebben, Harm P.;Nederhoed, Johanna H.;Yeung, Kak K.
背景：在标准动脉溶栓中加入局部超声造影剂可以加速脑卒中和心肌梗死的溶栓治疗。造反差剂由微型充满气体的气泡组成，当暴露于US时，气泡会破裂，导致凝块不稳定，使凝块表面更容易发生纤溶。在这项研究中，我们在猪广泛外周动脉闭塞模型中研究了额外的US和微泡对标准低剂量动脉内溶栓的影响。方法：用100iu牛凝血酶在10头猪4 cm髂外动脉内夹闭并注射，诱导广泛动脉血栓形成。经皮激光多普勒血流探头和超声血管周围血流探头分别评估微循环和动脉血流。仅尿激酶（UK）组（n = 4）接受标准溶栓治疗：动脉内注射500,000 IU，随后通过动脉内导管连续低剂量尿激酶（50,000 IU/h）输注，局部间歇应用US，开1秒，关5秒，在治疗的第一个小时内观察血管通畅，并确保微泡补充闭塞动脉近端。尿激酶加微泡（UK+）组（n = 6）接受相同的尿激酶治疗，同时静脉输注微泡和局部间歇性应用US。对比剂输注方案包括在前15分钟内注射两瓶5ml，然后在接下来的45分钟内连续缓慢手动注射3次5ml。治疗3小时后，将动物安乐死，取取血栓并称重。所有器官切成薄片，宏观检查潜在的（出血性）不良事件，并采集组织样本。结果：UK+组中位血栓重量为1.1 g（范围0.8-1.3 g），而UK组中位血栓重量为1.6 g（范围1.3-1.9 g） （P = 0.01）。在UK+组中，6头猪中有4头的动脉血流量平均增加了61%，而在UK组中，4头猪中有1头的动脉血流量增加了1%。与UK组的下降趋势相反，UK+组的微循环和下肢动脉压水平在治疗开始后有所改善。两组均未见出血并发症。结论：在这项实验性先导研究中，添加对比增强的US加速了外周动脉闭塞低剂量动脉内溶栓的溶栓作用。进一步的临床研究是必要的。
Background: The addition of local ultrasound (US) with a contrast agent to standard intra-arterial thrombolysis can accelerate the thrombolytic treatment of stroke and myocardial infarction. The contrast agent consists of microsized gas-filled bubbles that collapse when exposed to US, causing destabilization of the clot and making the clot surface more susceptible to fibrinolytics. In this study, we investigated the effect of additional US and microbubbles on standard low-dose intra-arterial thrombolysis in a porcine model of extensive peripheral arterial occlusion.Methods: Extensive arterial thrombosis was induced in 10 pigs in the 4-cm external iliac artery by clamping and injection of 100 IU of bovine thrombin. A transcutaneous laser Doppler flow probe and an ultrasonic perivascular flow probe assessed microcirculation and arterial flow respectively. The urokinase-only (UK) group (n = 4) received standard thrombolytic therapy: intra-arterial bolus injection of 500,000 IU, followed by a continuous low-dose urokinase (50,000 IU/h) infusion through an intra-arterial catheter and local intermittent application of US, 1 second on, 5 seconds off, to visualize vascular patency during the first hour of therapy and to ensure microbubbles replenished the proximal portion of the occluded artery. The urokinase plus microbubbles (UK+) group (n = 6) received the same urokinase therapy with a concomitant intravenous infusion of microbubbles and local intermittent application of US. The contrast infusion protocol consisted of a bolus of two vials of 5 mL in the first 15 minutes and then three times 5 mL slowly hand-injected continuously during the next 45 min. After 3 hours of therapy, the animals were euthanized, and thrombi were harvested and weighed. All organs were cut in thin slices and macroscopically inspected for potential (hemorrhagic) adverse events, and tissue samples were taken.Results: Median thrombus weights were 1.1 g (range, 0.8-1.3 g) in the UK+ group vs 1.6 g (range, 1.3-1.9 g) in the UK group (P = .01). Arterial blood flow increased in four of six pigs in the UK+ group by a mean 61% vs in one of four in the UK group, with 1%. Microcirculation and lower limb arterial pressure levels improved after the start of therapy in the UK+ group, contrary to a trend of decline in the UK group. No signs of bleeding complications were observed in either group.Conclusions: In this experimental pilot study, the addition of contrast-enhanced US accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. Further clinical studies are warranted.