Hemodynamic and Hematologic Effects of Histotripsy of Free-Flowing Blood: Implications for Ultrasound-Mediated Thrombolysis

Abstract

Purpose: To investigate the extent and consequences of histotripsy-induced hemolysis in vivo.

Materials and methods: Porcine femoral venous blood was treated with histotripsy in 11 animals with systemic heparinization and 11 without heparin. Serum and hemodynamic measurements were obtained at 0, 2, 5, 10, 15, and 30 minutes and 48-72 hours after the procedure. Fisher exact test was used to determine differences in mortality between heparinized and nonheparinized groups. A linear mixed effects model was used to test for differences in blood analytes and hemodynamic variables over time.

Results: Of 11 animals in the nonheparinized group, 5 died during or immediately after histotripsy (45% nonheparin mortality vs 0% heparin mortality, P = .035). Serum hematocrit, free hemoglobin, lactate dehydrogenase (LDH), and right ventricular systolic pressure changed significantly (P < .001) over the treatment time. Serum hematocrit decreased slightly (from 32.5% ± 3.6% to 29.4% ± 4.2%), whereas increases were seen in free hemoglobin (from 6.2 mg/dL ± 4.6 to 348 mg/dL ± 100), LDH (from 365 U/L ± 67.8 ± to 722 U/L ± 84.7), and right ventricular systolic pressure (from 23.2 mm Hg ± 7.2 to 39.7 mm Hg ± 12.3). After 48-72 hours, hematocrit remained slightly decreased (P = .005), whereas LDH and free hemoglobin remained slightly increased compared with baseline (both P < .001).

Conclusions: Intravascular histotripsy applied to free-flowing venous blood is safe with systemic heparinization, causing only transient hemodynamic and metabolic disturbances, supporting its use as a future noninvasive thrombolytic therapy modality.

Figure 1

Schematic demonstrating the histotripsy therapy transducer and imaging transducer suspended over a water bath, oriented for femoral vein targeting

Figure 2

A percolating histotripsy bubble cloud is induced in an empty water bath and is marked to subsequently assist in appropriately targeting the femoral vein.

Figure 3

Histotripsy applied to the femoral vein lumen, as demonstrated by the echobright cavitation cloud. The femoral vein is imaged along its long axis.

Figure 4

Hematocrit declines over histotripsy treatment time. The solid line depicts the linear decrease of hematocrit over time depicted by the linear mixed effects model including both heparin treated and non-treated pigs. The diamond indicates the mean of all hematocrit measurements at each time point among the pigs that survived at that time point, and the vertical bars encompass the 10^th to 90^th percentile.