Mallory R. Scola

ARFI ultrasound for in vivo hemostasis assessment postcardiac catheterization, part II: Pilot clinical results

In this second of a two part series, we present pilot clinical data demonstrating Acoustic Radiation Force Impulse (ARFI) ultrasound for monitoring the onset of subcutaneous hemostasis at femoral artery puncture sites (arteriotomies), in vivo. We conducted a randomized, reader-blinded investigation of 20 patient volunteers who underwent diagnostic percutaneous coronary catheterization. After sheath removal (6 French), patients were randomized to treatment with either standard of care manual compression alone or, to expedite hemostasis, manual compression augmented with a p-GlcNAc fiber-based hemostatic dressing (Marine Polymer Technologies, Danvers MA). Concurrent with manual compression, serial ARFI imaging began at the time of sheath removal and continued every minute for 15 min. Serial data sets were processed with custom software to (1) estimate the time of hemostasis onset, and (2) render hybrid ARFI/B-Mode images to highlight displacements considered to correspond to extravasted blood. Images were read by an observer blinded to the treatment groups. Average estimated times to hemostasis in patient volunteers treated with manual compression alone (n = 10) and manual compression augmented by hemostatic dressing (n = 9) were, respectively, 13.00 ± 1.56 and 9.44 ± 3.09 min, which are statistically significantly different (p = 0.0065, Wilcoxon two-sample test). Example images are shown for three selected patient volunteers. These pilot data suggest that ARFI ultrasound is relevant to monitoring subcutaneous bleeding from femoral arteriotomies clinically and that time to hemostasis was significantly reduced by use of the hemostatic dressing.

Multi-Push (MP) acoustic radiation force (ARF) ultrasound for assessing tissue viscoelasticity, in vivo

Acoustic radiation force (ARF) ultrasound is a method of elastographic imaging in which micron-scale tissue displacements, induced and tracked by ultrasound, reflect clinically relevant tissue mechanical properties. Our laboratory has recently shown that tissue viscoelasticity is assessed using the novel Multi-Push (MP) ARF method. MP ARF applies the Voigt model for viscoelastic materials and compares the displacements achieved by successive ARF excitations to qualitatively or quantitatively represent the relaxation time for constant stress, which is a direct descriptor of the viscoelastic response of the tissue. We have demonstrated MP ARF in custom viscoelastic tissue mimicking materials and implemented the method in vivo in canine muscle and human renal allografts, with strong spatial correlation between MP ARF findings and histochemical features and previously reported mechanical changes with renal disease. These data support that noninvasive MP ARF is capable of clinically relevant assessment of tissue viscoelastic properties.

ARFI Ultrasound for In Vivo Hemostasis Assessment Postcardiac Catheterization, Part I: Preclinical Studies

The world wide prevalence of cardiovascular disease leads to over seven million annual percutaneous coronary catheterization procedures, the majority of which exploit femoral artery access. Femoral puncture sites (‘arteriotomies’) can be associated with severe vessel complications after sheath removal if hemostasis is not properly achieved. Hemostasis onset is routinely determined by examination for bleeding at the skin puncture; however, clotting along the puncture path can obscure subcutaneous bleeding, and therefore hemostasis is blindly assessed. We hypothesize that hemostasis assessment can be un-blinded by Acoustic Radiation Force Impulse (ARFI) ultrasound. In this first of a two-part series, we present in vivo ARFI hemostasis imaging data obtained in relevant canine models of femoral artery puncture. Above arteriotomies, ARFI-induced displacements were large (3.5 to>5.0 μm) relative to surrounding soft tissue soon after needle removal, which was consistent with our expectation for pooled extravasated blood. ARFI-induced displacements above arteriotomies decreased in magnitude (to ∼ 2μm) some time after needle removal and suggested the onset of hemostasis. This preclinical investigation served as proof of concept and justification for a pilot human study, which is presented in part two of this series.

A review of current methods for assessing hemostasis in vivo and introduction to a potential alternative approach.

A validated method for assessing hemostasis in vivo is critical for testing the hemostatic efficacy of therapeutic agents in preclinical animal models and in patients with inherited bleeding disorders, such as von Willebrand disease (VWD) and hemophilia A, or with acquired bleeding disorders such as those resulting from medications or disease processes. In this review, we discuss current methods for assessing hemostasis in vivo and the associated challenges. We also present ARFI-Monitored Hemostatic Challenge; a new, potentially alternate method for in vivo hemostasis monitoring that is in development by our group.

Analysis of cross-correlation coefficients for subcutaneous blood signal detection by ARFI Imaging

ARFI subcutaneous blood detection is relevant for monitoring femoral puncture post cardiac catheterization as well as numerous other clinical applications. Blood signal isolation by conventional means is challenged by overlapping frequency spectra and low blood to surrounding tissue signal amplitude ratios. ARFI Imaging was performed ex vivo on a porcine muscle injected with a blood mimicking fluid. Fluid signal isolation was attempted by performing thresholding based on (1) variance of displacement, (2) mean cross-correlation, (3) variance of cross-correlation, (4) variance of first derivative of cross-correlation, and (5) variance of second derivative of cross-correlation. Using the results of the thresholding, an algorithm was developed which exploits both the second derivative of cross-correlation and the mean cross-correlation to extract blood signal.

Reverberation artifact rejection and masking in arterial ARFI imaging

In arterial ultrasound imaging, interpretation of plaque geometry may be distorted by reverberation artifacts in the lumen. Reverberation and arterial wall signals may be highly correlated, which precludes frequency domain or conventional regression filtering methods; however, decorrelation and rates vary. The variance of time derivatives in 1D axial cross-correlation (CC) and displacement (Disp) measures were exploited to reject the arterial lumen and reverberation artifact. Adaptively determined thresholds were applied to the variance of either individual or spatially clustered ARFI displacement profiles. The resulting binary masks were applied in vivo to six porcine arteries with varying degrees of reverberation artifact. Mask performance was measured as the percentage of the lumen rejected given at least 98% of each arterial wall remaining intact. The highest performing masks used the variance of the 2nd derivative of displacement or correlation with spatial clustering to preserve both arterial wall and soft tissue signals.

Viscoelastic Strain Response (ViSR) ultrasound assessment of viscoelastic properties in human duchenne muscular dystrophy, in vivo

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that is caused by a mutation in the gene for dystrophin leading to a loss of the dystrophin protein from the muscle cell (myofiber) membrane. Viscoelastic Strain Response (ViSR) ultrasound is a new, quantitative acoustic radiation force (ARF) based elastographic imaging method to calculate τ, the viscoelastic relaxation time constant for constant stress. We have investigated the use of ViSR imaging in human DMD. Imaging was performed in vivo on the right rectus femoris (RF), sartorius (SART), and gastrocnemius (GAST) muscles of two boys with DMD. The boys were 5- and 9-years-old at the time of imaging. ViSR results in the 5-year-old showed an average of 27.0%, 6.6%, and 18.2% fat/necrosis composition in the RF, SART, and GAST, respectively. In the 9-year old subject, ViSR showed an average fat/necrosis composition of 66.7% in the RF, 9.1% in the SART, and 37.2% in the GAST. These results are consistent with both the known phenotypic response of the three muscles and with functional testing results and point to ViSRs potential relevance as a novel outcome measure for diagnostics and clinical trials in DMD.

Clinical multi-push acoustic radiation force for evaluation of renal transplant status

Invasive biopsy is currently the gold standard for assessment of renal transplant health. The need for biopsy may be reduced as suitable, noninvasive imaging methods become available. An imaging technique that exploits the viscoelastic properties of renal tissue could be relevant as a biopsy alternative, given that normal renal pelvis and parenchyma have different viscoelastic properties, while renal disease or rejection may result in altered mechanical relationships between pelvis and parenchyma. We hypothesize that MP-ARF, which qualitatively evaluates the viscoelastic properties of tissue, is relevant for noninvasively assessing viscoelastic similarity between pelvis and parenchyma in renal transplant patient volunteers. Regional ratios of marginal peak displacement (MPD) and first peak measurements were significantly different (p <; 0.05) in moderate vascular disease and chronic allograft nephropathy, respectively, relative to control. This suggests that MP ARF could be a relevant clinical technique for noninvasively discriminating renal transplant health.

Multi-Push (MP) ARF assessment of viscoelastic properties in a tissue mimicking phantom effect of time separation

We present a new approach to differentiating the viscoelastic properties of tissue, Multi-Push Acoustic Radiation Force (MP ARF) ultrasound, in which displacements achieved by successive ARF excitations are compared to qualitatively assess viscoelastic tissue parameters. We evaluate the MP ARF measures of marginal peak displacement (MPD) in four tissue-mimicking phantoms using different time separations between successive excitations. A time separation of 0.4 ms between excitations yielded the best contrast when differentiating between a phantom with low stiff, low viscosity and a phantom with high stiffness, low viscosity. Similarly, 0.4 ms between excitations gave the best MPD contrast between a phantom with low stiffness, low viscosity and a phantom with low stiffness, high viscosity. A time separation of 1.2 ms gave the optimal separation when differentiating between a phantom with high stiffness, low viscosity and a phantom with high stiffness, high viscosity. MPD was also shown to be is less depth-dependent than first peak displacement.

Delineating serial mechanical property changes in a dog model of duchenne muscular dystrophy using ARFI ultrasound, in vivo

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that is caused by a mutation in the gene for dystrophin leading to a loss of the dystrophin protein from the muscle cell (myofiber) membrane. The golden retriever muscular dystrophy (GRMD) model also has a naturally-occurring dystrophin gene mutation and progressive phenotypic features analogous to those seen in DMD. We have investigated the use of Acoustic Radiation Force Impulse (ARFI) imaging in the GRMD canine model. Imaging was performed in vivo on the right rectus femoris (RF) and cranial sartorius (CS) muscles in both transverse and parallel planes. A cohort of 6 normal dogs and 4 GRMD dogs were imaged at 3, 6, and 12 months of age. Results showed significant differences in peak displacement in the RF for GRMD vs normal dog, but similar ARFI results in the CS. These results are consistent with known variations in disease progression in RF versus CS muscles in the dog model and suggest that ARFI could be relevant to monitoring therapy in affected individuals.