Quantification of microspheres appearance in brain vessels: Implications for residual flow velocity measurements, dose calculations, and potential drug delivery

Background and Purpose: Characteristics of ultrasound-activated gaseous microspheres (μS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. Methods: A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler μS traces included large ( > 8μ) μS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small ( < 5μ) μS from acute patients without shunts receiving thrombolysis and perflutren-lipid μS. Results: In 101 μS traces from 50 RLS-positive and 10 thrombolysis+μS treated patients, a large μS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small μS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P < 0.001. Small μS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P < 0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embolus-to-Blood Ratio) 0.927 (0.871 to 0.982), P < 0.001. A 15.1-ms duration discriminated size ranges with 98% to 99% accuracy. On average, 130 sequential large (range 51 to 260) and 500 (265–588) small μS can produce continuous flow enhancement for 4 seconds. Small μS velocities on m-mode in obstructed vessels (39.8±11.3 cm/s) were similar to large μS in patent vessels (40.8±11.5 cm/s; P=0.719) and higher than surrounding red blood cell velocities (28.8±13.8 cm/s, P < 0.001). Conclusions: With normal or reduced flow, activated μS passage duration through a small power motion Doppler gate can quantify the dose of delivered μS. Ultrasound can determine a minimum number of μS needed to achieve constant flow enhancement and targeted drug delivery. Propagation speed of μS smaller than red blood cells may reflect plasma flow velocities around acute occlusions