This pilot trial was followed by a phase II randomized controlled trial CLOTBUST (Combined Lysis of Thrombus in Brain Ischemia AZD6244 using Transcranial Ultrasound and Systemic TPA), which demonstrated that enhancement of the thrombolytic activity of tPA could be safely achieved by using higher frequency (2 MHz) and low intensity (<700 mW/cm2) single element pulsed-wave ultrasound [2]. In 126 patients randomized in a 1:1 fashion acute rt-PA treated stroke patients were either insonated within a 3-h time window for 2 h or not. rt-PA induced arterial recanalization was increased by ultrasound

(sustained complete recanalization rates at 2 h: 38% versus 13%, p = 0.002) with a non-significant trend toward an increased rate of clinical recovery from stroke, as compared with placebo and at no increased cost of bleeding complications (4.8% in both arms). A phase III trial has been planned for quite some time and protocols have been published [10]. The problem, however, is still the lack of an investigator independent device, although this may be solved in the close future (Andrei Alexandrov, personal communication). Transcranial color coded duplex

ultrasound (TCCD) has been used in four smaller trials of ultrasound enhanced thrombolysis [3]. In general, the results were somewhat better than control rt-PA patients with C59 wnt regard to recanalization and trends for outcome, but again at the cost of higher bleeding rates

fortunately not in the same range as in the TRUMBI trial. Microbubbles (MBs, microspheres), originally developed as ultrasound contrast agents, have been utilized for increasing ultrasound performance in neurovascular imaging and sonolysis by enhanced cavitation and microstreaming [11] and [12]. Derived from experimental studies in the 90s [13], the approach was consecutively applied to the clinical setting [12] and [14]. In a first study Molina and colleagues used levovist® given at 3 time points in 38 patients compared to 73 patients treated with either 2 MHz TCD and rt-PA or Adenosine rt-PA alone [12]. Complete recanalization rate 2 h after t-PA bolus was significantly higher in the tPA/US/MB group (54.5%) compared with tPA/US (40.8%) and tPA (23.9%) groups (p = 0.038). No systemic symptoms deriving from MBs use were documented. Symptomatic ICH rates did not differ. A French TCCD (plus rt-PA plus MB versus rt-PA alone) study was terminated prematurely because of safety concerns [15]. Other MBs have been tested but none have emerged so far as superior to others. Newer submicron lipid coated perflutren MBs (“nanobubbles”) were tested in a pilot trial and a phase IIa study [14] and [16]. Preliminary data compared to historic controls from the CLOTBUST trial showed a higher rate of complete recanalization (50% versus 18%, p = 0.028) and sustained complete recanalization at 2 h (42% versus 13%, p = 0.003).