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Contrast-Enhanced Subharmonic Aided Pressure Estimation (SHAPE) Using Ultrasound Imaging with a Focus on Identifying Portal Hypertension

Published: December 5th, 2020



1Department of Radiology, Thomas Jefferson University, 2School of Biomedical Engineering, Sciences and Health Systems, Drexel University, 3Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University, 4GE Global Research

A protocol for noninvasively estimating ambient pressures utilizing subharmonic ultrasound imaging of infused contrast microbubbles (following appropriate calibration) is described with examples from human patients with chronic liver disease.

Noninvasive, accurate measurement of pressures within the human body has long been an important but elusive clinical goal. Contrast agents for ultrasound imaging are gas-filled, encapsulated microbubbles (diameter < 10 μm) that traverse the entire vasculature and enhance signals by up to 30 dB. These microbubbles also produce nonlinear oscillations at frequencies ranging from the subharmonic (half of the transmit frequency) to higher harmonics. The subharmonic amplitude has an inverse linear relationship with the ambient hydrostatic pressure. Here an ultrasound system capable of performing real-time, subharmonic aided pressure estimation (SHAPE) is presented. During ultrasound contrast agent infusion, an algorithm for optimizing acoustic outputs is activated. Following this calibration, subharmonic microbubble signals (i.e., SHAPE) have the highest sensitivity to pressure changes and can be used to noninvasively quantify pressure. The utility of the SHAPE procedure for identifying portal hypertension in the liver is the emphasis here, but the technique has applicability across many clinical scenarios.

A number of different ultrasound contrast agents (UCAs) are approved for clinical use in cardiology (in particular left ventricular opacification) and radiology (in particular adult and pediatric liver lesion characterization) across the world.1 The sensitivity and specificity of ultrasound imaging can be improved by intravenous (IV) injection of gas-filled microbubbles (diameter < 10 μm) encapsulated by a lipid or protein shell as UCAs that traverse the entire vasculature and enhance signals by up to 30 dB.1 These UCAs not only enhance the backscattered ultrasound signals, but at sufficient acoustic p....

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The institutional review boards of both Thomas Jefferson University and the Hospital of the University of Pennsylvania approved this protocol. The protocol is compliant with the Health Insurance Portability and Accountability Act. The United States Food and Drug Administration (FDA) issued an Investigational New Drug approval (IND # 124,465 to F. Forsberg) for this protocol. GE Healthcare (Oslo, Norway) provided the UCA used in this research (Sonazoid; Table 1). Sonazoid is not approved by the FDA for an.......

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As with all ultrasound imaging examinations, the first consideration for liver SHAPE is to obtain the best possible baseline grayscale images of the target region and to ensure (using Doppler imaging) that there are no intrahepatic portal venous shunts or other vascular abnormalities present. In the case of liver imaging for diagnosing portal hypertension the key is to visualize both the portal vein and a hepatic vein at the same depth to minimize the impact of attenuation (Figure 1).

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Noninvasive, accurate measurement of pressures within the human body has long been an important but elusive clinical goal. The protocol for SHAPE measurements presented here achieves this goal. The most critical component of the SHAPE procedure is the optimization algorithm, since subharmonic data not acquired at the optimal acoustic power output will correlate poorly with hydrostatic pressures.17,22,23 The initial version .......

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This work is supported in part by the U.S. Army Medical Research Material Command under W81XWH-08-1-0503, and W81XWH-12-1-0066, by AHA grants no 0655441U and 15SDG25740015 as well as by NIH R21 HL081892, R21 HL130899, R21 HL089175, RC1 DK087365, R01 DK098526, R01 DK118964, R01 CA140338, R01 CA234428, by Lantheus Medical Imaging and by GE Healthcare, Oslo, Norway.


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Name Company Catalog Number Comments
2 mL syringe Becton Dickinson 309637 Used for reconstituting Sonazoid
10 mL saline-filled syringe Becton Dickinson 306545 Used for flushing line to verify IV access
500 mL saline bag Baxter Healthcare Corp 2131323 Used for co-infusion with Sonazoid
C1-6-D curvi-linear proble GE Healthcare H40472LT Used for liver imaging
Chemoprotect Spike Codan USA C355 Chemospike used for reconstituting Sonazoid
Discofix C Blue B. Braun Medical Inc 16494C 3-way stopcock
Intrafix Safeset 180 cm B. Braun Medical Inc 4063000 Infusion tubing
Logiq E10 ultrasound scanner GE Healthcare H4928US Used for conventional ultrasound imaging as well as for SHI and SHAPE
Luer lock 10 mL syringe Becton Dickinson 300912 For infusion of Sonazoid
Medfusion 3500 syringe pump Smiths Medical 3500-500 Used for infusing Sonazoid at 0.18 mL/kg/hour
Perfusor-leitung tubing 150 mm B. Braun Medical Inc 8722960 Extension line enabling syringe connection to patient's IV access
SHI/SHAPE software GE Healthcare H4920CI Contrast-specific imaging software
Sigma Spectrum infusion system Baxter Healthcare Corp 35700BAX Pump used for co-infusing saline at 120 mL/hour
Sonazoid GE Healthcare Gas-filled microbubble based ultrasound contrast agent
sterile water, 2 mL B. Braun Medical Inc Used for reconstituting Sonazoid
ultrasound gel Cardinal Health USG-250BT Used for contact between probe and patient
Venflon IV cannula 22GA Becton Dickinson 393202 Cannula needle for obtaining IV access

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