Dynamic contrast-enhanced ultrasound for assessment of therapy effects on skeletal muscle microcirculation in peripheral arterial disease: pilot study.

OBJECTIVE: To assess with dynamic contrast-enhanced ultrasound (CEUS) and transient arterial occlusion whether the muscular micro-perfusion in patients with peripheral arterial disease (PAD) is improved after angioplasty or surgery. MATERIALS AND METHODS: This study had local institutional review board approval. Written informed consent was obtained from all 20 patients with PAD, Fontaine stage IIb (mean age, 64 years), who participated in the study. Low-MI CEUS (7MHz; MI, 0.28) was applied to the mainly affected lower leg after start of a continuous automatic intravenous injection of 4.8mL SonoVue(®). Muscle-perfusion was monitored by CEUS before, during, and after provocation by arterial occlusion at the thigh level lasting for 60s. CEUS examination was performed a second time within 14 days after angioplasty (n=15), thrombendarterectomy (n=2), angioplasty and thrombendarterectomy (n=1), or bypass (n=2). Clinical amelioration was re-evaluated within 6 months after the intervention using a 4-point scale. RESULTS: Ankle-brachial-index (ABI) increased from 0.8±0.2 to 0.9±0.3 after treatment (p=0.01). Time to maximum CEUS signal (tmax) shortened from 26±14s to 14±4s (p=0.004). The slope to maximum after transient occlusion (m2) changed to steeper values (6.4±5.8∼mL/s versus 10.2±5.0∼mL/s; p=0.04). Shortened tmax predicted improvement in the patients' intermittent leg pain and therefore successful therapy outcome. CONCLUSION: Dynamic CEUS with transient arterial occlusion can visualize the treatment-induced improvement of muscular micro-perfusion in patients with PAD.

Comparison of a standard and a high-concentration contrast medium protocol for MDCT angiography of the lower limb arteries.

PURPOSE: To prospectively compare a compact bolus (CB) injection protocol using high-iodine concentration contrast medium with a standard bolus (SB) injection protocol at equi-iodine doses for run-off computed tomographic angiography (CTA). MATERIALS AND METHODS: 64 patients with suspected peripheral arterial disease who underwent 40 or 64-slice run-off CTA were included in this IRB-approved study. Patients were randomized to undergo the CB protocol (32 patients, iomeprol 400mgI/mL, 100 mL, 4 mL/sec) or the SB protocol (32 patients, iomeprol 300mgI/mL, 134 mL, 4 mL/sec). Luminal contrast density (CD) values were measured and arterial opacification (AO) was scored (5-point scale). Cases of venous overlay or bolus overriding were documented. RESULTS: Overall arterial CD was significantly higher with the compact bolus (CB: 279 ± 57HU, SB: 234 ± 32HU, p = 0.0017). Segmental CD was significantly higher (p< 0.05) in 7 of 16 evaluated segments. Patency-based comparison revealed superior AO in vessels with relevant (50 - 99 %) stenoses (CB: 4.54 vs. SB: 4.18, p = 0.04). Contrast bolus overriding without pathological reasons, i. e., acute occlusions, was noted in one patient in each group. Venous overlay was observed less frequently in the CB group (CB vs. SB: 12 vs. 19 patients, n. s.; 29 of 64 legs [45 %] vs. 44 of 64 legs [69 %], p = 0.01). CONCLUSION: At equi-iodine doses, the CB protocol led to a quantitatively and qualitatively higher arterial opacification compared to the SB protocol. Therefore, a CB protocol should be favored for run-off CTA.

Dynamic contrast-enhanced ultrasound and transient arterial occlusion for quantification of arterial perfusion reserve in peripheral arterial disease.

OBJECTIVE: To quantify muscular micro-perfusion and arterial perfusion reserve in peripheral arterial disease (PAD) with dynamic contrast-enhanced ultrasound (CEUS) and transient arterial occlusion. MATERIALS AND METHODS: This study had local institutional review board approval and written informed consent was obtained from all subjects. We examined the dominant lower leg of 40 PAD Fontaine stage IIb patients (mean age, 65 years) and 40 healthy volunteers (mean age, 54 years) with CEUS (7 MHz; MI, 0.28) during continuous intravenous infusion of 4.8 mL microbubbles. Transient arterial occlusion at mid-thigh level simulated physical exercise. With time-CEUS-intensity curves obtained from regions of interest within calf muscles, we derived the maximum CEUS signal after occlusion (max) and its time (tmax), slope to maximum (m), vascular response after occlusion (AUC(post)), and analysed accuracy, receiver operating characteristic (ROC) curves, and correlations with ankle-brachial index (ABI) and walking distance. RESULTS: All parameters differed in PAD and volunteers (p<0.014). In PAD, tmax was delayed (31.2±13.6 vs. 16.7±8.5 s, p<0.0001) and negatively correlated with ankle-brachial-index (r=-0.65). m was decreased in PAD (4.3±4.6 mL/s vs. 13.1±8.4 mL/s, p<0.0001) and had highest diagnostic accuracy (sensitivity/specificity, 75%/93%) for detection of diminished muscular micro-perfusion in PAD (cut-off value, m<5∼mL/s). Discriminant analysis and ROC curves revealed m, and AUC(post) as optimal parameter combination for diagnosing PAD and therefore impaired arterial perfusion reserve. CONCLUSIONS: Dynamic CEUS with transient arterial occlusion quantifies muscular micro-perfusion and arterial perfusion reserve. The technique is accurate to diagnose PAD.

[Contrast-enhanced ultrasound of skeletal muscle]. / Kontrastverstärkter Ultraschall der Skelettmuskulatur.

Functional imaging can increase the role of imaging in muscular diseases, as alterations of muscle morphology alone are non-specific for a particular disease. A good example for these functional imaging techniques is to use contrast-enhanced ultrasound (CEUS) to visualize and quantify in vivo (patho-) physiological information about the skeletal muscle microcirculation. Perfusion, i.e. the blood flow per tissue unit including capillary flow, is an important functional parameter. Pathological changes of skeletal muscle perfusion can be found in various clinical conditions, such as degenerative or inflammatory myopathy or peripheral arterial disease (PAD). This article reviews the theoretical basics of functional radiological techniques for assessing skeletal muscle perfusion and focuses on applications of microvascular imaging by CEUS which has improved the diagnosis of these muscular disorders. For evaluation of myositis, CEUS is more efficient in the diagnostic work-up than routine b-mode ultrasound because CEUS can detect inflammation-induced muscular hyperperfusion in acute myositis. This has already been demonstrated by high-mechanical index techniques using a first generation ultrasound contrast agent. Low-mechanical index CEUS techniques that require the use of a second generation contrast agent allow real-time quantification of muscular microcirculation at rest and during exercise. Using this CEUS method, the influence of different exercise intensities on the microcirculation of the exercising muscle becomes detectable. Moreover, the arterial perfusion reserve in PAD can be adequately examined using low-mechanical index CEUS. Initial findings have shown that the arterial perfusion reserve in patients suffering from PAD is reduced in comparison to healthy volunteers. In conclusion, modern CEUS techniques can offer deeper insights in muscular (patho-) physiology than just illustrating unspecific myopathic manifestations using conventional diagnostic imaging, such as edematous or lipomatous changes, hypertrophy or atrophy.

[Contrast-enhanced ultrasound for the characterization of incidental liver lesions - an economical evaluation in comparison with multi-phase computed tomography]. / Kontrastverstärkter Ultraschall zur Charakterisierung von inzidentellen Leberläsionen - eine ökonomische Betrachtung im Vergleich zur Mehrphasen-Computertomografie.

AIM: The aim of the study was to conduct a cost-minimization analysis of contrast-enhanced ultrasound (CEUS) compared to multi-phase computed tomography (M-CT) as the diagnostic standard for diagnosing incidental liver lesions. METHODS: Different scenarios of a cost-covering realization of CEUS in the ambulant sector in the general health insurance system of Germany were compared to the current cost situation. The absolute savings potential was estimated using different approaches for the calculation of the incidence of liver lesions which require further characterization. RESULTS: CEUS was the more cost-effective method in all scenarios in which CEUS examinations where performed at specialized centers (122.18-186.53 euro) compared to M-CT (223.19 euro). With about 40 000 relevant liver lesions per year, systematic implementation of CEUS would result in a cost savings of 4 m euro per year. However, the scenario of a cost-covering CEUS examination for all physicians who perform liver ultrasound would be the most cost-intensive approach (e. g., 407.87 euro at an average utilization of the ultrasound machine of 25 %, and a CEUS ratio of 5 %). CONCLUSION: A cost-covering realization of the CEUS method can result in cost savings in the German healthcare system. A centralized approach as proposed by the DEGUM should be targeted.

[Ultrasound contrast agents. Pharmaceutical drug safety and bioeffects]. / Ultraschallkontrastmittel. Arzneimittelsicherheit und Bioeffekte.

In this overview safety aspects of ultrasound contrast agents (USCA) are described and discussed. In general USCA are very safe drugs. However, allergic adverse reactions can rarely occur, particularly due to the colloidal structure of USCA. In addition, the use of USCA could reduce the threshold for acoustically induced bioeffects and has the potential to increase these effects. In in vitro studies and animal trials USCA caused petechial hemorrhages, vascular damage, and the formation of free radicals. Even DNA damage with single strand breaks could be demonstrated. In human studies and clinical practice none of these bioeffects could be observed. In contrast-enhanced echocardiography a higher rate of premature ventricular contractions has been reported when imaging was triggered at the end systole. Compared with other contrast agents contrast-enhanced ultrasound showed no nephrotoxic effects and could prove to be an alternative diagnostic method for patients with renal failure.

[Ultrasound contrast media--principles and clinical applications]. / Ultraschallkontrastmittel -- Grundlagen und klinische Anwendung.

This article reviews the technical basics and the application of contrast-enhanced ultrasonography. Ultrasound contrast agents have been evaluated in various organs and have proven to be particularly useful in the detection and characterization of liver lesions. Experiences in small parts (such as breast, or lymph nodes) are so far limited, because only since recently are the technical prerequisites available for contrast-enhanced ultrasound high-frequency transducers. Ultrasound contrast media can be used for functional studies, e. g., of organ or tumor perfusion. Mathematical models were primarily developed for measuring myocardial perfusion and have recently been adapted for studying tumors. In animal experiments as well as in clinical applications, quantitative parameters of tumor perfusion have been evaluated as surrogate parameters for response to radiotherapy, chemotherapy, or treatment with anti-angiogenic agents.

[Vascular imaging with contrast-enhanced sonography for experimental use]. / Vaskuläre Bildgebung mittels kontrastverstärkter Sonographie in der experimentellen Anwendung.

The possibility of employing contrast-enhanced ultrasound for sensitive detection of perfusion has resulted in new forms of application in fundamental medical biological research that go far beyond mere preclinical evaluation of these techniques. This contribution explains the methods for visualization and quantification of perfusion with contrast-enhanced sonography and provides an overview of how these functional examinations have been used to date. The procedure is generally considered indicated when information on tissue perfusion using ultrasound is required. This topic is also gaining increasing clinical interest, e.g., for assessment of myocardial, cerebral, and renal perfusion or for monitoring therapy. Among the various new treatment procedures that have been investigated in animal models with ultrasound, particularly pro-angiogenic and antiangiogenic therapy approaches predict promising new fields for application of contrast-enhanced ultrasound.

Monitoring of liver metastases after stereotactic radiotherapy using low-MI contrast-enhanced ultrasound--initial results.

The purpose of this study was to monitor liver metastases after radiotherapy using contrast-enhanced ultrasound (CEUS). In 15 patients, follow-up examinations after stereotactic, single-dose radiotherapy were performed using CEUS (low mechanical index (MI), 2.4-ml SonoVue) and computed tomography (CT). Besides tumor size, the enhancement of the liver and the metastases was assessed at the arterial, portal venous, and delayed phases. The sizes of the tumor and of a perifocal liver reaction after radiotherapy measured with CEUS significantly correlated with those measured at CT (r=0.93, p<0.001). CEUS found a significant reduction of the arterial vascularization in treated tumors (p<0.05). In the arterial phase, the perifocal liver tissue was hypervascularized compared to the treated tumor (p<0.001); in the late phase, it was less enhanced than the liver (p<0.001) and more than the tumor (p<0.01). The perifocal liver reaction was also seen in CT, but with a variable enhancement at the arterial (50% hyperdense compared to normal liver tissue), venous, or delayed phase (each with 70% hyperdense reactions). CEUS allows for the assessment of tumor and liver perfusion, in addition to morphological tumor examination, which was comparable with CT. Thus, changes of tumor perfusion, which may indicate tumor response, as well as the perifocal liver reaction after radiotherapy, which must be differentiated from perifocal tumor growth, can be sensitively visualized using CEUS.

[Quantification of tissue perfusion with novel ultrasound methods]. / Moderne sonographische Methoden zur Quantifizierung von Gewebeperfusion.

Perfusion describes an important parameter of tissue vitality, e. g. of the myocardium, brain, or the kidney. In malign tumours, perfusion is of particular interest for characterization and prognosis. In addition, new pro- or anti-angiogenic therapies require a functional imaging which is suitable to quantify vascularity. Sonographic methods for the detection of microvascularity, particularly related smaller than those amenable to Doppler ultrasound, are reviewed. The main focus deals with the explanation of contrast-enhanced sonography using replenishment kinetics of microbubbles which provides a comprehensive quantification of tissue perfusion. Alterations of the microvascularity e. g., under anti-angiogenic therapy, can be depicted in experimental studies using this novel approach. Further clinical applications can be the quantification of the perfusion in the myocardium, the brain, or the kidney. New approaches to optimize the theoretical model to describe the replenishment, and novel technical developments are discussed.

Magnetic resonance imaging of nude mice with heterotransplanted high-grade squamous cell carcinomas: use of a low-loaded, covalently bound Gd-Hsa conjugate as contrast agent with high tumor affinity.

RATIONALE: Malignant tumors often show an increased uptake and metabolism of plasma proteins, especially albumin. OBJECTIVES: Determine whether the accumulation of low loaded Gd-albumin improves visualization of malignant tumors by MRI. METHODS: Twelve nude mice with heterotransplanted squamous cell carcinomas were studied. The signal intensity of tumor, blood, liver, kidney and muscle tissue was studied in MR images after application of Gd-albumin during a period of 144 hours. MRI results were histologically correlated after simultaneously injection of Gd- and fluorescein-labeled albumins in 9 nude mice. RESULTS: Although liver and kidney had a maximum increase in signal intensity within 30 minutes, tumors showed a delayed 51% increase in the 24 hours after application. Histologic and fluorescence evaluation demonstrated albumin localization in tumors predominantly in stroma and necroses. CONCLUSIONS: Gd-albumin is efficiently accumulated in SCC transplants. MRI with low loaded Gd-albumin may offer relevant opportunities for recognizing tumors sensitive to a therapy with cyostic drug-labeled albumins.

Rigid piston approximation for computing the transfer function and angular response of a fiber-optic hydrophone.

The transfer function of a fiber-optic hydrophone (FOH) is computed for various fiber core radii. The hydrophone is modeled as a rigid disk, with plane waves impinging at normal or oblique incidence. The total sound field is written as the sum of the incident field and the field diffracted from the hydrophone. The diffracted field is approximated by the field generated by a vibrating planar piston in an infinite rigid baffle. For normal incidence and a pointlike fiber core, an analytical solution is presented. For finite fiber core radii, and for oblique incidence, the transfer functions are computed numerically. The calculated transfer functions exhibit an oscillatory frequency dependency that is most pronounced for small fiber cores. The solution for a core radius of 2.5 microm can be very well approximated by the analytical solution for a pointlike core at frequencies of up to 30 MHz. The results for normal incidence can be directly employed to deconvolute ultrasonic pressure signals measured with an FOH. From the transfer functions for oblique incidence, the angular response of the hydrophone is calculated. The angular response obtained here differs significantly from the model commonly used for piezoelectric hydrophones. The effective hydrophone radius derived from the angular response shows a strong frequency dependency. For low frequencies, it is found to be larger than the outer fiber radius, whereas it generally lies between the outer radius and the fiber core radius for frequencies above 10 MHz.