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.

Figure 1

The block diagram of the electronic part (a), the acoustic part (b) and the flow system part (c) of the measurement system.

Figure 2

Comparison of the changes in fundamental (a), second harmonic (b) and subharmonic signal amplitude (c) as a function of ambient pressure when transmitting at 4.4 MHz (receiving at 2.2 MHz) and an acoustic pressure of 0.42 MPa. Mean values ± 1 standard deviation are shown (N = 3) for Levovist, Optison, Definity, ZFX and Sonazoid. Notice the difference in scale for the y-axis.

Figure 3

Maximum decrease in subharmonic signal amplitude over a pressure range of 0 to 186 mmHg as a function of transmit frequency and transmit pressure (averaged over 3 measurements) for Sonazoid (a), Definity (b) and Optison (c).

Figure 4

Example of flow phantom imaged in fundamental (a) and in SHI (b) mode (within ROI). The location of the pressure catheter (roughly 2 cm depth) is indicated with arrows.

Figure 5

Best fit example for instantaneous hydrostatic pressures measured by pressure catheter (blue line) and SHAPE (red dots) for a pulse length of 8 cycles transmitting at 2.5 MHz and an acoustic output level of 24 % (r² = 0.87, p < 0.01)