Subharmonic Contrast Microbubble Signals for Noninvasive Pressure Estimation under Static and Dynamic Flow Conditions

Abstract

Our group has proposed the concept of subharmonic aided pressure estimation (SHAPE) utilizing microbubble-based ultrasound contrast agent signals for the noninvasive estimation of hydrostatic blood pressures. An experimental system for in vitro SHAPE was constructed based on two single-element transducers assembled confocally at a 60 degree angle to each other. Changes in the first, second and subharmonic amplitudes of five different ultrasound contrast agents were measured in vitro at static hydrostatic pressures from 0-186 mmHg, acoustic pressures from 0.35-0.60 MPa peak-to-peak and frequencies of 2.5-6.6 MHz. The most sensitive agent and optimal parameters for SHAPE were determined using linear regression analysis and implemented on a Logiq 9 scanner (GE Healthcare, Milwaukee, WI). This implementation of SHAPE was then tested under dynamic-flow conditions and compared to pressure-catheter measurements. Over the pressure range studied, the first and second harmonic amplitudes reduced approximately 2 dB for all contrast agents. Over the same pressure range, the subharmonic amplitudes decreased by 9-14 dB and excellent linear regressions were achieved with the hydrostatic pressure variations (r = 0.98, p < 0.001). Optimal sensitivity was achieved at a transmit frequency of 2.5 MHz and acoustic pressure of 0.35 MPa using Sonazoid (GE Healthcare, Oslo, Norway). A Logiq 9 scanner was modified to implement SHAPE on a convex transducer with a frequency range from 1.5-4.5 MHz and acoustic pressures from 0-3.34 MPa. Results matched the pressure catheter (r2 = 0.87). In conclusion, subharmonic contrast signals are a good indicator of hydrostatic pressure. Out of the five ultrasound contrast agents tested, Sonazoid was the most sensitive for subharmonic pressure estimation. Real-time SHAPE has been implemented on a commercial scanner and offers the possibility of allowing pressures in the heart and elsewhere to be obtained noninvasively.

Chronic Liver Disease: Noninvasive Subharmonic Aided Pressure Estimation of Hepatic Venous Pressure Gradient

“…Previously, it has been shown that the subharmonic amplitude (at half the transmitting frequency) decreases linearly with increases in ambient fluid pressure and that this change is more than three times greater than either the fundamental or the second harmonic peak fluctuation (8)(9)(10)(11). This response forms the basis of a technique referred to as subharmonic aided pressure estimation (SHAPE).…”

“…(a sonographer with 26 years of scanning experience) or P.M. (a radiologist with 10 years of experience). The SHAPE mode was set to transmit four-cycle pulses at 2.5 MHz and to receive subharmonic signals at 1.25 MHz, as determined during previous optimization of the technique (11). In addition to acquiring SHAPE data, this unit also provided the ability to simultaneously display B-mode US images (at 4.0 MHz and a mechanical index of 0.32, intermittently transmitting between SHAPE pulses) and subharmonic US images (generated from the time domain of the SHAPE data) for easier US navigation and identification of the vascular structures of interest; namely, the portal and hepatic veins (20).…”

“…Despite its excellent safety profile and daily clinical use in Japan since 2007 (33,34), the U.S. Food and Drug Administration (FDA) has yet to approve this contrast agent for clinical use. In our study, we chose to use this contrast agent because previous in vitro work showed its subharmonic amplitude to be the most sensitive to hydrostatic pressures of all commercially available agents (11). However, SHAPE has also been shown to be feasible when performed with other FDAapproved contrast agents (9,11,13), and the usage of such agents could potentially result in more rapid clinical translation of SHAPE.…”

Noninvasive estimation of dynamic pressures in vitro and in vivo using the subharmonic response from microbubbles

“…Techniques for estimating ambient pressures using microbubbles have been proposed [6][7][8][9][10], but these techniques have yielded clinically unacceptable errors (as high as 10-15 mmHg in vitro under ideal conditions). A different approach utilizing subharmonic emissions from ultrasound contrast agents to track pressures called SHAPE (subharmonic aided pressure estimation) was proposed and validated in vitro [11,12]. Subharmonic emissions from microbubbles are a function of incident acoustic pressure and characterized into 3 stages -occurrence, growth and saturation.…”

“…The objective of this work was to evaluate the use of microbubbles to track dynamic pressures in a continuous flow environment and to develop a SHAPE application using a commercially available ultrasound scanner and an existing ultrasound contrast agent. Based on prior studies [11][12][13] Sonazoid microbubbles (GE Healthcare, Oslo, Norway; perfluorobutane gas encapsulated in a membrane of hydrogenated egg phosphatidyl serine) were selected for use in this study. Furthermore, as a proof-of-concept of the proposed technique, the noninvasive tracking of left ventricular (LV) pressures in vivo was investigated.…”