Ultrasound Acceleration of rt-PA Thrombolysis Depends on Acoustic Intensity

Recombinant tissue-type plasminogen activator (rt-PA) is effective and widely used in the treatment of acute ischemic stroke (AIS). However, symptomatic intracranial hemorrhage (ICH), an adverse reaction of rt-PA, is known to occur depending on underlying diseases and rt-PA doses, and to occur more frequently with a greater delay from stroke onset until initiation of rt-PA. Therefore, limitations on the use of rt-PA, such as having to be started within 4.5 h of stroke onset, mean that rt-PA is only indicated in some stroke patients. However, the number of patients in whom rt-PA is indicated could increase if symptomatic ICH induced by rt-PA could be reduced. Therefore, we believe that, if the incidence of adverse reactions such as ICH could be reduced by using lower rt-PA doses together with ultrasound (US), the number of patients eligible for rt-PA treatment would increase. In other words, we hypothesized that, if thrombolysis can be accelerated by US, then recanalization rates similar to currently used doses of rt-PA can be achieved at reduced rt-PA doses. Therefore, to investigate to what extent US enhances the thrombolytic efficacy of rt-PA, the relationship between acceleration of rt-PA thrombolysis and US acoustic intensity was quantitatively evaluated in an in vitro bovine thrombus model. It was found that, within a range of US output that is noninvasive in humans, the combined use of US can increase thrombolytic activity up to 2.5 times more than with rt-PA alone. These findings suggest that US can greatly reduce the required doses of rt-PA.