Daniel A. Merton

Clinical applications of ultrasound contrast agents

Within the last decade safe and practical ultrasound contrast agents have been introduced. Most of these are based on gas-filled microbubbles, which markedly enhance Doppler signals and, in some cases, also gray-scale images. The clinical improvements expected from ultrasound contrast is reviewed. Tissue-specific contrast agents constitute another area of potential clinical significance. One particular agent is taken up by the reticulo-endothelial system and produces so-called acoustic emission signals when imaged. An introduction to the unique clinical applications of acoustic emission is given. Harmonic imaging is a new contrast-specific imaging modality, which utilizes the nonlinear properties of some agents in an attempt to alleviate current limitations of ultrasound contrast studies. Examples of harmonic images are presented.

Galactose-based intravenous sonographic contrast agent : experimental studies

A galactose‐based sonographic contrast agent, which produces stable microbubbles capable of traversing the cardiopulmonary circulation, was used to enhance Doppler signals in blood vessels of varying size after intravenous injection. A series of experiments using dogs, rabbits, and woodchucks was conducted to establish the ability of the agent to enhance the reflectivity of normal tissue, tumor tissue, and blood. Although no enhancement was perceptible in tissue on the sonogram, significant enhancement of color and spectral Doppler signals was demonstrated in a variety of vessels. These included the aorta, vena cava, and portal vein as well as such small vessels as those of the retina of the eye, renal cortex, liver parenchyma, and gallbladder wall. Both spectral and color Doppler enhancement was shown in naturally occurring woodchuck hepatomas. Peak Doppler signal enhancement after bolus injection was approximately 10 dB with a dose of 0.01 ml/kg. Recirculation of the agent provided enhancement after intravenous bolus injection for more than 3 min. With a steady intravenous infusion of 0.2 ml/min/kg, Doppler signal enhancement of about 14 dB was maintained continuously for more than 5 min. The results of these animal experiments, in particular in small vessels and with recirculation after intravenous injection, suggest excellent potential for future clinical applications.

Treatment of iatrogenic femoral artery injuries with ultrasound-guided compression

Iatrogenic injuries of the groin are becoming more common after increasingly sophisticated vascular intervention. These injuries are accurately detected by duplex and color Doppler ultrasonography. Recent treatment of these lesions by ultrasound-guided compression repair (UGCR) has been described. During a 1-year period we identified 18 femoral artery injuries, including 17 pseudoaneurysms and one arteriovenous fistula. Three of the pseudoaneurysms thrombosed spontaneously before attempted treatment. The remaining 15 lesions underwent a trial of UGCR. Successful closure was accomplished in 10 patients (56%). Seven of these lesions were successfully treated during the initial session, and thrombosis was accomplished after repeat compression in three additional lesions. Three patients who were given anticoagulants had a failed UGCR, but their pseudoaneurysms thrombosed after administration of anticoagulants was discontinued. Two patients had failed UGCR and required operation. Seven (88%) of eight patients who were not given anticoagulants were successfully treated. In contrast only two (29%) of seven patients given therapeutic doses of anticoagulant medication were successfully treated by the technique. There was no statistical difference between mean pseudoaneurysm diameter, mean width and length of pseudoaneurysm neck, or depth of pseudoaneurysm neck from skin surface in patients in whom successful initial closure was achieved when compared with those patients in whom the initial attempt failed. UGCR is a safe, simple, noninvasive technique that can be used to treat many femoral artery injuries that traditionally were treated with surgery. The technique can be applied by any laboratory that has the necessary ultrasonography equipment and is currently the method of choice for treating uncomplicated iatrogenic femoral artery injuries at our institution.

Neurosonographic features of periventricular echodensities associated with cerebral palsy in preterm infants.

We studied the value of neonatal neurosonograms in preterm infants for predicting the development of cerebral palsy (CP). All infants born at less than 33 weeks of gestation who were admitted to the intensive care nursery of Thomas Jefferson University Hospital from 1982 to 1986 were serially studied with cranial ultrasound methods that reliably detect neonatal periventricular echodensities (PVE) and cysts that are 2 mm in diameter or larger. PVE were graded as mild or as moderate to severe, and cyst size was classified by widest diameter as either large (greater than or equal to 3 mm) or small (less than 3 mm). All 127 surviving infants with PVE or cyst formation or both were followed until spastic forms of CP could be diagnosed or excluded during late infancy. All 26 of the infants in whom spastic CP developed had moderate or severe PVE in the area superior and lateral to the caudothalamic notch as noted on the parasagittal images of the neonatal neurosonograms. All these infants also developed cysts in the periventricular region within the area of the previously noted PVE. Mild or moderate to severe PVE were not associated with the development of spastic CP in 101 infants. Cysts developed in the area of PVE in the neurosonographic studies of 42 of these 101 infants. Mild PVE without cysts and moderate to severe PVE without cysts had negative predictive values for CP of 69% and 76%, respectively. By contrast, the presence of moderate to severe PVEs with large cyst formation had positive and negative predictive values of 90% and 93%, respectively, and was the most sensitive and specific neurosonographic finding for predicting CP, with an efficiency of 92%. The presence or absence of intracranial hemorrhage did not increase the efficiency of the ultrasound test results.

On the feasibility of real-time, in vivo harmonic imaging with proteinaceous microspheres

Harmonic imaging is a new contrast‐specific imaging modality, which utilizes the nonlinear properties of microbubble‐based sonographic contrast agents by transmitting at the fundamental frequency but receiving at the second harmonic frequency. The feasibility of improving the detection of slow, small‐volume blood flow using real‐time harmonic imaging has been investigated in vivo. Proteinaceous microspheres (FS069) were administrated to four dogs, two woodchucks (with multiple hepatomas), and one rabbit. Three different scanners were used to obtain real‐time images of kidneys and liver (including vessels) in harmonic and conventional gray scale and color flow modes. The duration of contrast enhancement lasted significantly longer in harmonic than in conventional modes (on average 87 s; P = 0.008). Harmonic images were less susceptible to artifacts, such as acoustic shadowing, and a clear increase in the (flow) signal‐to‐noise ratio was observed. These preliminary in vivo results demonstrate the feasibility of performing real‐time, contrast‐enhanced harmonic imaging, but further studies are required to establish clinical efficacy.

Contrast-Enhanced Sonographic Imaging of Lymphatic Channels and Sentinel Lymph Nodes

The purpose of this study was to determine whether lymphatic channels (LCs) and sentinel lymph nodes (SLNs) could be detected on sonographic imaging after subcutaneous, submucosal, or parenchymal injections of a sonographic contrast agent (ie, lymphosonography) in a variety of anatomic locations in several animal models.

Color Doppler Imaging in the Management of Intraocular Tumors

Forty-four intraocular mass lesions were studied using a new, non-invasive ultrasound technique known as color Doppler imaging (CDI). This technique displays color-encoded Doppler flow information throughout a two-dimensional gray scale image thus providing selective analysis of Doppler spectra in small vessels using pulsed Doppler. Abnormal Doppler shifts were demonstrated within 39 neoplastic lesions studied, but Doppler shifts could not be detected in three tumor-simulating lesions. In a group of 12 choroidal melanomas studied after radiation therapy, lower Doppler shifts were seen compared with a group of 28 tumors before therapy. This change in Doppler shift may reflect the decreased vascular supply of the tumor. Color Doppler imaging may be of value as an additional useful tool in the diagnosis and management of intraocular tumors.

Contrast-Enhanced Two- and Three-dimensional Sonography for Evaluation of Intra-abdominal Hemorrhage

Objective. To determine whether a contrast agent enhances sonographic detection of bleeding sites in the abdomen and whether contrast‐enhanced three‐dimensional sonography provides additional information compared with contrast‐enhanced two‐dimensional sonography. Methods.Bleeding sites were created within the livers (n = 3), spleens (n = 5), and kidneys (n = 3) of 3 dogs. A sonographic contrast agent with vascular and parenchymal enhancement capabilities was administered intravenously at a dose of 0.02 mL/kg. Before and after each contrast agent injection, the bleeding sites were imaged with two‐ and three‐dimensional sonography in gray scale harmonic imaging and color flow modes. Sonographic findings were compared with gross pathologic findings. Results.Non– contrast‐enhanced sonography was not able to show the specific location of the active bleeding in any of the organs evaluated. The contrast agent enhanced the sonographic detection of blood flow in normal vessels and extravasated blood from damaged vessels or organs in all cases. Intrasplenic and intrahepatic hematomas were better identified on delayed imaging sequences because there was marked enhancement of the normal parenchyma, whereas the hematomas remained unenhanced. Reconstructed three‐dimensional sonography showed spatial relationships of the bleeding sites and surrounding structures. Gross pathologic findings were consistent with the contrast‐enhanced sonographic results. Conclusions.Contrast‐enhanced sonography improves the detection and evaluation of abdominal bleeding sites. Contrast‐enhanced three‐dimensional sonography appears to provide additional information when compared with two‐dimensional sonography.

Endoluminal sonographic evaluation of ureteral and renal pelvic neoplasms

The objective of this study was to demonstrate the feasibility of endoluminal ultrasonography as an adjunct to endoscopy for the evaluation of urothelial neoplasms. An endoluminal ultrasound system using a 12.5 or 20 MHz transducer housed in a 6.2 French catheter was used intraureterally in 38 patients being evaluated endoscopically for suspected tumors in the renal pelvis or ureter. The ultrasonographic, endoscopic, and pathologic findings were evaluated. The location, size, and sonographic characteristics of the tumors in the upper urinary tract were well demonstrated. The information obtained by this technique can be used to guide endoscopic biopsy and laser ablation of the tumor. Endoluminal ultrasonography also has proved helpful in defining the location of a tumor relative to an adjacent vessel and in identifying crossing vessels that cause extrinsic filling defects in the ureter. In a few pathologically correlated cases, endoluminal ultrasonography was accurate in assessing invasion. We have evaluated successfully a variety of non‐neoplastic filling defects in relatively few cases. Determination of the eventual usefulness of this technique awaits greater clinical experience and large clinical trials.

Color amplitude imaging: preliminary results using vascular sonographic contrast agents.

Conventional (mean Doppler frequency shift) color Doppler imaging and a new method of displaying blood flow in color that uses the amplitude of the Doppler signal were utilized to evaluate three vascular sonographic contrast agents. To compare the two color flow detection modalities, a total of 20 pairs of contrast agent injections were performed while imaging a variety of abdominal organs and tumors in experimental animal models. The 20 paired injections were scored independently to indicate whether color amplitude imaging better demonstrated the effects of contrast enhancement (n = 14), both techniques were equivalent in demonstrating the effects of contrast enhancement (n = 4), or color Doppler imaging better demonstrated the effects of contrast enhancement (n = 2). These results indicate that compared to color Doppler imaging, color amplitude imaging improved visualization of both normal and abnormal blood flow in 70% of these cases (P < 0.0001). Specifically, with contrast enhancement of the Doppler signals, organ vascularity and regional differences in parenchymal blood flow were better demonstrated with color amplitude imaging than with color Doppler imaging. In addition, since color amplitude imaging is nondirectional and less angle dependent than color Doppler imaging, it was possible to visualize vessel continuity more completely and to demonstrate vessel branching more clearly with this modality. However, owing to the lack of directivity and poor temporal resolution, information obtained with color amplitude imaging appears to be complementary to that of color Doppler imaging. In conclusion, color amplitude imaging is a reliable method of determining the effectiveness of vascular sonographic contrast agents and should be considered one of the primary flow imaging modalities used for the assessment of these agents.