Subharmonic Aided Pressure Estimation (SHAPE) of Portal Hypertension

Portal hypertension is difficult to diagnose at its early stage as symptoms rarely manifest until the later stages of liver disease. As pressures in the portal vein cannot be directly measured, portal pressures are estimated using the hepatic venous pressure gradient (HVPG). This is defined as the difference between the wedged and free hepatic venous pressures. Patients with an HVPG greater than 10 mmHg are at increased risk of developing varices, while patients with an HVPG above 12 mmHg are at risk of variceal bleeding (which is associated with mortality rates of 15-20 %). The current clinical technique for measuring HVPG is invasive and requires insertion of a balloon catheter via a transjugular approach into the hepatic vasculature. Noninvasive techniques such as ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) have a very poor sensitivity to portal pressure estimation and are therefore, not accurate enough to be used routinely for diagnosis of portal hypertension. Thus, an alternative accurate, noninvasive ultrasound-based procedure would be a major development in the diagnosis of portal hypertension making the diagnosis safer, quicker and relatively cheaper. Hence, the fundamental hypothesis of this project is that portal vein pressures can be monitored and quantified noninvasively in humans using contrast-enhanced subharmonic-aided pressure estimation (SHAPE). SHAPE is based on the inverse relationship between the subharmonic amplitude of contrast microbubbles (obtained by transmitting at the fundamental frequency fo and receiving at fo/2) and the ambient pressure. The hypothesis of this study is that portal vein pressures can be monitored and quantified noninvasively in humans using SHAPE. Sonazoid was the contrast agent used for this study. In the first part of this study, the effect of pulse shaping on SHAPE was studied. It was concluded that the shape of the input pulse changes the subharmonic signal generated by UCAs and also the gradient observed with changing hydrostatic pressure. There was a significantly higher correlation of the SHAPE gradient with changing pressures for the broadband pulses as compared to the narrowband pulses in both in vitro and in vivo results. The highest correlation was achieved with a Gaussian windowed binomial filtered square wave with an r-value of -0.95. One of the 3 canines was eliminated for technical reasons, while the other 2 produced very similar results to those obtained in vitro (r from -0.72 to -0.98; p12 mm Hg) had a significantly higher mean subharmonic gradient than patients with lower HVPGs (0.27± 2.04 vs -4.90 ±3.28 dB; p<0.0001). SHAPE was also used for monitoring disease progression of portal hypertensive patients. These patients had follow-up clinic visits or CT/MRI scans every 6 months and at those times a repeat SHAPE examination was performed collecting data from the portal and hepatic vein in triplicate. Liver function tests (albumin, bilirubin and coagulation panel), MELD scores and presence of ascites and varices were used for treatment response. For all the cases SHAPE findings were consistent with clinical expectations. The change in the SHAPE gradient relative to baseline decreased significantly for the responders (n=9) (i.e., implying improvement) compared to the non-responders (n=2; -4.70 ±3.27 dB vs 1.77±0.55 dB; p