Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

Abstract

In monitoring of recanalization and in sonothrombolysis, contrast-enhanced ultrasound (CEUS) is applied in extended time protocols. As extended use may increase the probability of unwanted effects, careful safety evaluation is required. We investigated the safety profile and beneficial effects of CEUS in a reperfusion model. Wistar rats were subjected to filament occlusion of the right middle cerebral artery (MCA). Reperfusion was established after 90 minutes, followed by recombinant tissue-type plasminogen activator (rt-PA) treatment and randomization to additional CEUS (contrast agent: SonoVue; 60 minutes). Blinded outcome evaluation consisted of magnetic resonance imaging (MRI), neurologic assessment, and histology and, in separate experiments, quantitative 3D nano-computed tomography (CT) angiography (900 nm 3 voxel size). Nano-CT revealed severely compromised microcirculation in untreated animals after MCA reperfusion. The rt-PA partially improved hemispheric perfusion. Impairment was completely reversed in animals receiving rt-PA and CEUS. This combination was more effective than treatment with either CEUS without rt-PA or rt-PA and ultrasound or ultrasound alone. In MRI experiments, CEUS and rt-PA treatment resulted in a significantly reduced ischemic lesion volume and edema formation. No unwanted effects were detected on MRI, histology, and intracranial temperature assessment. This study shows that CEUS and rt-PA is safe in the situation of reperfusion and displays beneficial effects on the level of the microvasculature.

A pragmatic approach to sonothrombolysis in acute ischaemic stroke: the Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS)

“…This group consists of 90 % of all acute ischaemic stroke patients, but has not been included in previous sonothrombolysis and sonolysis clinical trials. The most prominent treatment effect with complete reversal of microcirculatory obstructions has been seen for contrast enhanced sonothrombolysis (tPA, ultrasound and microbubbles) vs. tPA with unenhanced ultrasound [35]. Also, a tissue protective effect and improved microcirculation has been observed with the combination of ultrasound and microbubbles [39].…”

“…Contrast enhanced ultrasound insonation of thrombi in the absence of iv tPA has achieved high rates of recanalisation in animal models [35]. Repeated oscillations of the microbubbles around the clot cause an increase in local temperature due to the absorption of the energy from the radiated sound field and create further heating through viscous friction in the blood [36].…”

“…Recanalisation rate following iv thrombolysis is higher with smaller thrombi in distal arteries [47]. It is therefore conceivable that ultrasound has even better effect on small, not visible peripheral arterial thrombi, on perforator thrombotic occlusions, or even thrombi in the microcirculation [35]. Several areas of peripheral vessels are, however, not accessible by ultrasound.…”

Nano-Computed Tomography: Technique and Applications

“…The application of nano-CT in experimental ischemia diagnosis and therapy allows improved visualization of cerebral microcirculation [44] to the capillary level. Use for fine structure imaging of the osseous [28,45], renal [46,47], and dental [48] anatomy and pathophysiology as well as scaffold imaging [29] are examples for the potential of this radiological technique and expected uses in coming years.…”

Progress in Sonothrombolysis for the Treatment of Stroke

“…59 Recently, nano-CT was used to demonstrate complete reversal of microcirculatory impairment in a rodent reperfusion model after treatment with recombinant tPA, US, and microbubbles. 60 The mechanism of the microcirculatory effect of US and microbubbles may involve improvement of blood flow to risk tissue through collaterals and changes in the microenvironment of damaged tissue, like decreased cell-damaging factors, for example, glutamate or enhanced enzyme activity of endothelial nitric oxide. 61 Further work is necessary to elucidate the exact mechanisms of salvaging of tissue at risk by US-mediated microbubble thrombolysis.…”