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.

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...

<ol>
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J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterization+of+adnexal+masses+using+contrast-enhanced+subharmonic+imaging:+a+pilot+study.">Characterization of adnexal masses using contrast-enhanced subharmonic imaging: a pilot study.</a> Journal of Ultrasound in Medicine. 39 (5), 977-985 (2020).</li><li>Eisenbrey, J. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Contrast-enhanced+subharmonic+and+harmonic+ultrasound+of+renal+masses+undergoing+percutaneous+cryoablation.">Contrast-enhanced subharmonic and harmonic ultrasound of renal masses undergoing percutaneous cryoablation.</a> Academic Radiology. 22 (7), 820-826 (2015).</li><li>Gupta, I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transrectal+subharmonic+ultrasound+imaging+for+prostate+cancer+detection.">Transrectal subharmonic ultrasound imaging for prostate cancer detection.</a> Urology. 138 (4), 106-112 (2020).</li><li>Shi, W. T., Forsberg, F., Raichlen, J. S., Needleman, L., Goldberg, B. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pressure+dependence+of+subharmonic+signals+from+contrast+microbubbles.">Pressure dependence of subharmonic signals from contrast microbubbles.</a> Ultrasound in Medicine and Biology. 25 (2), 275-283 (1999).</li><li>Halldorsdottir, V. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Subharmonic+contrast+microbubble+signals+for+noninvasive+pressure+estimation+under+static+and+dynamic+flow+conditions.">Subharmonic contrast microbubble signals for noninvasive pressure estimation under static and dynamic flow conditions.</a> Ultrasonic Imaging. 33 (3), 153-164 (2011).</li><li>Nio, A. Q. X., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optimal+control+of+SonoVue+microbubbles+to+estimate+hydrostatic+pressure.">Optimal control of SonoVue microbubbles to estimate hydrostatic pressure.</a> IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. 67 (3), 557-567 (2020).</li><li>Eisenbrey, J. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chronic+liver+disease:+noninvasive+subharmonic+aided+pressure+estimation+of+hepatic+venous+pressure+gradient.">Chronic liver disease: noninvasive subharmonic aided pressure estimation of hepatic venous pressure gradient.</a> Radiology. 268 (2), 581-588 (2013).</li><li>Gupta, I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diagnosing+portal+hypertension+with+noninvasive+subharmonic+pressure+estimates+from+an+ultrasound+contrast+agent.">Diagnosing portal hypertension with noninvasive subharmonic pressure estimates from an ultrasound contrast agent.</a> Radiology. , (2020).</li><li>Nam, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Monitoring+neoadjuvant+chemotherapy+for+breast+cancer+by+using+three-dimensional+subharmonic+aided+pressure+estimation+and+imaging+with+US+contrast+agents:+preliminary+experience.">Monitoring neoadjuvant chemotherapy for breast cancer by using three-dimensional subharmonic aided pressure estimation and imaging with US contrast agents: preliminary experience.</a> Radiology. 285 (1), 53-62 (2017).</li><li>Dave, J. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Non-invasive+intra-cardiac+pressure+measurements+using+subharmonic-aided+pressure+estimation:+proof+of+concept+in+humans.">Non-invasive intra-cardiac pressure measurements using subharmonic-aided pressure estimation: proof of concept in humans.</a> Ultrasound in Medicine and Biology. 43 (11), 2718-2724 (2017).</li><li>Esposito, C., Dickie, K., Forsberg, F., Dave, J. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Developing+an+interface+and+investigating+optimal+parameters+for+real-time+intra-cardiac+subharmonic+aided+pressure+estimation.">Developing an interface and investigating optimal parameters for real-time intra-cardiac subharmonic aided pressure estimation.</a> IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. , (2020).</li><li>Bosch, J., Groszmann, R. J., Shah, V. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evolution+in+the+understanding+of+the+pathophysiological+basis+of+portal+hypertension:+How+changes+in+paradigm+are+leading+to+successful+new+treatments.">Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments.</a> Journal of Hepatology. 62, 121-130 (2015).</li><li>Procopet, B., Berzigotti, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diagnosis+of+cirrhosis+and+portal+hypertension:+imaging,+non-invasive+markers+of+fibrosis+and+liver+biopsy.">Diagnosis of cirrhosis and portal hypertension: imaging, non-invasive markers of fibrosis and liver biopsy.</a> Gastroenterology Report. 5 (2), 79-89 (2017).</li><li>Dietrich, C. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Guidelines+and+good+clinical+practice+recommendations+for+contrast-enhanced+ultrasound+(CEUS)+in+the+liver-update+2020+WFUMB+in+cooperation+with+EFSUMB,+AFSUMB,+AIUM,+and+FLAUS.">Guidelines and good clinical practice recommendations for contrast-enhanced ultrasound (CEUS) in the liver-update 2020 WFUMB in cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS.</a> Ultrasound in Medicine and Biology. , (2020).</li><li>Gupta, I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effect+of+pulse+shaping+on+subharmonic+aided+pressure+estimation+in+vitro+and+in+vivo.">Effect of pulse shaping on subharmonic aided pressure estimation in vitro and in vivo.</a> Journal of Ultrasound in Medicine. 36 (1), 3-11 (2017).</li><li>Dave, J. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=On+the+implementation+of+an+automated+acoustic+output+optimization+algorithm+for+subharmonic+aided+pressure+estimation.">On the implementation of an automated acoustic output optimization algorithm for subharmonic aided pressure estimation.</a> Ultrasonics. 53 (4), 880-888 (2013).</li><li>Gupta, I., Eisenbrey, J. R., Machado, P., Stanczak, M., Wallace, K., Forsberg, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=On+factors+impacting+subharmonic-+aided+pressure+estimation+(SHAPE).">On factors impacting subharmonic- aided pressure estimation (SHAPE).</a> Ultrasonic Imaging. 41 (1), 35-48 (2019).</li><li>Eisenbrey, J. R., Daecher, A., Kramer, M. R., Forsberg, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+needle+and+catheter+size+on+commercially+available+ultrasound+contrast+agents.">Effects of needle and catheter size on commercially available ultrasound contrast agents.</a> Journal of Ultrasound in Medicine. 34 (11), 1961-1968 (2015).</li></ol>

Drs. Forsberg, Gupta, Wallace and Eisenbrey have a patent pending on the SHAPE technology. Dr. Wallace is an employee of GE.

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&#160;The initial version ...

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&#160;The sensitivity and specificity of ultrasound imaging can be improved by intravenous (IV) injection of gas-filled microbubbles (diameter &#60; 10 &#956;m) encapsulated by a lipid or protein shell as UCAs that traverse the entire vasculature and enhance signals by up to 30 dB.1&#160;These UCAs not only enhance the backscattered ultrasound signals, but at sufficient acoustic pressures (&#62; 200 kPa) they also act as nonlinear oscillators. Hence, significant energy components will be produced in the received echoes ranging from subharmonic and harmonic to ultraharmonic frequencies.1,2&#160;These nonlinear signal components can be extracted from tissue and linear bubble echoes (e.g., using pulse inversion) and used to create contrast-specific imaging modalities such as subharmonic imaging (SHI), which receives at half the transmit frequency (i.e., at f0/2).3&#160;Our group has demonstrated in human clinical trials that SHI can detect the blood flow in neovessels and arterioles associated with a variety of&#160;tumors and tissues.4,5,6,7,8,9
We have advocated the use of UCAs not as vascular tracers, but as sensors for noninvasive pressure estimation in the circulatory system by monitoring subharmonic contrast bubble amplitude variations.10&#160;This innovative technique, called subharmonic-aided pressure estimation (SHAPE), relies on the inverse linear correlation between the amplitude of the subharmonic signals and hydrostatic pressure (up to 186 mmHg) measured for most commercial UCAs in vitro (r2 &#62; 0.90) as summarized in Table 1.10,11&#160;However, it should be noted that not all UCAs exhibit this behavior. Most notably, it has been shown that subharmonic signals from the UCA SonoVue (known as Lumason in the USA) initially rise with hydrostatic pressure increases, followed by a plateau and a decreasing phase.12&#160;Nonetheless, SHAPE offers the possibility of allowing pressure gradients in the heart and throughout the cardiovascular system as well as interstitial fluid pressure in tumors to be obtained noninvasively.13,14,15,16,17&#160;Recently, we implemented a real-time version of the SHAPE algorithm on a commercial ultrasound scanner and provided proof-of-concept that SHAPE can provide in vivo pressure estimates with errors of less than 3 mmHg in the left and right ventricles of patients.16,17
The most experience with SHAPE to date has been for&#160;diagnosing portal hypertension with more than 220 subjects enrolled &#160;and initial findings confirmed in a multi-center trial.13,14&#160;Portal hypertension is defined as an increase in the pressure gradient between the portal vein and hepatic veins or the inferior vena cava exceeding 5 mmHg, while clinically significant portal hypertension (CSPH) requires a gradient or its equivalent, a hepatic venous pressure gradient (HVPG) &#8805; 10 mmHg.18&#160;CSPH is associated with an increased risk of gastroesophageal varices, ascites, hepatic decompensation, post-operative decompensation, and hepatocellular carcinoma.18,19&#160;Patients who develop ascites have a 50% three-year mortality and those who develop spontaneous infection of the ascites fluid carry a 70% one-year mortality. Patients with cirrhosis have a 5-10% yearly incidence of gastroesophageal variceal formation, and a 4-15% yearly incidence of bleeding; each bleeding episode carries up to a 20% risk of death.18,19
This manuscript describes how to conduct a SHAPE study using commercially available equipment and UCAs with an emphasis on identifying portal hypertension in the liver of patients. The critical calibration procedure required to achieve the highest sensitivity to estimating pressure changes is explained in detail.

<table>
	<tbody>
		<tr>
			<td>2 mL syringe</td>
			<td>Becton Dickinson</td>
			<td>309637</td>
			<td>Used for reconstituting Sonazoid</td>
		</tr>
		<tr>
			<td>10 mL saline-filled syringe</td>
			<td>Becton Dickinson</td>
			<td>306545</td>
			<td>Used for flushing line to verify IV access</td>
		</tr>
		<tr>
			<td>500 mL saline bag</td>
			<td>Baxter Healthcare Corp</td>
			<td>2131323</td>
			<td>Used for co-infusion with Sonazoid</td>
		</tr>
		<tr>
			<td>C1-6-D curvi-linear proble</td>
			<td>GE Healthcare</td>
			<td>H40472LT</td>
			<td>Used for liver imaging</td>
		</tr>
		<tr>
			<td>Chemoprotect Spike</td>
			<td>Codan USA</td>
			<td>C355</td>
			<td>Chemospike used for reconstituting Sonazoid</td>
		</tr>
		<tr>
			<td>Discofix C Blue</td>
			<td>B. Braun Medical Inc</td>
			<td>16494C</td>
			<td>3-way stopcock</td>
		</tr>
		<tr>
			<td>Intrafix Safeset 180 cm</td>
			<td>B. Braun Medical Inc</td>
			<td>4063000</td>
			<td>Infusion tubing</td>
		</tr>
		<tr>
			<td>Logiq E10 ultrasound scanner</td>
			<td>GE Healthcare</td>
			<td>H4928US</td>
			<td>Used for conventional ultrasound imaging as well as for SHI and SHAPE</td>
		</tr>
		<tr>
			<td>Luer lock 10 mL syringe</td>
			<td>Becton Dickinson</td>
			<td>300912</td>
			<td>For infusion of Sonazoid</td>
		</tr>
		<tr>
			<td>Medfusion 3500 syringe pump</td>
			<td>Smiths Medical</td>
			<td>3500-500</td>
			<td>Used for infusing Sonazoid at 0.18 mL/kg/hour</td>
		</tr>
		<tr>
			<td>Perfusor-leitung tubing 150 mm</td>
			<td>B. Braun Medical Inc</td>
			<td>8722960</td>
			<td>Extension line enabling syringe connection to patient&#39;s IV access</td>
		</tr>
		<tr>
			<td>SHI/SHAPE software</td>
			<td>GE Healthcare</td>
			<td>H4920CI</td>
			<td>Contrast-specific imaging software</td>
		</tr>
		<tr>
			<td>Sigma Spectrum infusion system</td>
			<td>Baxter Healthcare Corp</td>
			<td>35700BAX</td>
			<td>Pump used for co-infusing saline at 120 mL/hour</td>
		</tr>
		<tr>
			<td>Sonazoid</td>
			<td>GE Healthcare</td>
			<td></td>
			<td>Gas-filled microbubble based ultrasound contrast agent</td>
		</tr>
		<tr>
			<td>sterile water, 2 mL</td>
			<td>B. Braun Medical Inc</td>
			<td></td>
			<td>Used for reconstituting Sonazoid</td>
		</tr>
		<tr>
			<td>ultrasound gel</td>
			<td>Cardinal Health</td>
			<td>USG-250BT</td>
			<td>Used for contact between probe and patient</td>
		</tr>
		<tr>
			<td>Venflon IV cannula 22GA</td>
			<td>Becton Dickinson</td>
			<td>393202</td>
			<td>Cannula needle for obtaining IV access</td>
		</tr>
	</tbody>
</table>

contrast-enhanced subharmonic aided pressure estimation (shape) using ultrasound imaging with a focus on identifying portal hypertension

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 &#60; 10 &#956;m) 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.

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).
<p...

Watch this Scientific Journal Video about Contrast-Enhanced Subharmonic Aided Pressure Estimation SHAPE Using Ultrasound Imaging with a Focus on Identifying Portal Hypertension at JoVE.com

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

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.

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

Noninvasive, accurate measurement of pressures within the human body has long been an important but elusive clinical goal. Contrast agents for ultrasound ...

This technique is designed for measuring pressures non-invasively within the body. It's particularly useful for monitoring pressures in the heart, for monitoring treatment of cancers, and in this particular project for measuring pressures in the liver. To prepare the ultrasound contrast agent, remove the protective cap from the syringe port of the chemo spike and use a chemo spike to perforate the stopper of the first of three vials of the agent.Add two milliliters of sterile water to the vial and immediately shake the vial for one minute. When a homogenous product has been obtained, withdraw the product into the syringe. The reconstituted ultrasound contrast agent contains microbubbles at a concentration of eight microliters per milliliter.After repeating the reconstitution for the other two vials in the same manner, use saline to fill up connecting tubes and connect the tubes to a three-way stopcock. Connect the stopcock to the extension tubing leading to the cannula and connect the syringe directly to the stopcock. Then mount the syringe onto a syringe pump at the same level or below the patient.To acquire an initial set of ultrasound images, power up an ultrasound scanner and select the C1-6-D curvilinear probe. Select an abdominal preset on the scanner. Use a subcostal approach and a curvilinear array to acquire grayscale images of both the portal and hepatic veins in the same imaging plane and at similar depths.Optimize the images based on good clinical practice, taking care to select the hepatic vein region away from the inferior vena cava to avoid the influence of retrograde flow. After the initial ultrasound imaging, open the stopcock and infuse the saline solution at a rate of 120 milliliters per hour while co-infusing the contrast at a rate of 0.024 microliters per kilogram body rate per minute. For activating subharmonic imaging in dual display mode, use the subharmonic contrast touch panel button to activate contrast mode.Select subharmonic imaging amplitude modulation on the rotary control. Perform subharmonic imaging at a transmit frequency of 2.5 megahertz and obtain the received signals at 1.25 megahertz. Confirm the patency of the portal and the hepatic veins as well as the presence of microbubbles, which can take up to one to two minutes from the start of the infusion.Select time intensity curve analysis on the touch panel followed by F6 and K to compensate for varying depths and attenuations to activate the SHAPE automated optimization code to optimize the SHAPE imaging. The SHAPE optimization algorithm will acquire subharmonic data for every acoustic output level. Once the data acquisition is complete, position a region of interest on the portal vein in the contrast sample window.Plot the average subharmonic data within the region as a function of acoustic output and fit a logistic curve to the data. Then select the inflection point of this curve as the optimized power, as this has been shown to be the point of greatest SHAPE sensitivity. Adjust the acoustic output power to the inflection point value to maximize the sensitivity of the SHAPE and acquire subharmonic data from the microbubbles in five to 15 second segments during the infusion of the UCA suspension.When imaging for diagnosing portal hypertension in the liver, the key is to visualize both the portal and hepatic veins at the same depth to minimize the impact of attenuation. After a UCA induced equilibrium enhancement, the optimization algorithm should be activated and a region of interest in the portal vein should be selected to produce subharmonic amplitude and output power selection curves. In these SHAPE images from patients with and without clinical significant portal hypertension, the main visual difference is the marked subharmonic signal present in the hepatic vein in the patient with hypertension that is absent in the patient without hypertension.Note that some patients present with clinical and laboratorial signs of portal hypertension but have HVPG values that are normal or zero. This can be attributed to a number of anatomical and/or vascular variations, resulting in an incorrect SHAPE diagnosis. This technique is non-invasive, safe, and accurate.It allows the acquisition of relative as well as absolute pressure estimates, and it's something that no other imaging technique can currently do.

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2.1K visualizações.  Thomas Jefferson University. This technique is designed for measuring pressures non-invasively within the body. It's particularly useful for monitoring pressures in the heart, for monitoring treatment of cancers, and in this particular project for measuring pressures in the liver. To prepare the ultrasound contrast agent, remove the protective cap from the syringe port of the chemo spike and use a chemo spike to perforate the stopper of the first of three vials of the agent.Add two milliliters of sterile water to ...