Assessment of tissue perfusion by contrast-enhanced ultrasound

Contrast-enhanced ultrasound (CEUS) with microbubble contrast agents is a new imaging technique for quantifying tissue perfusion. CEUS presents several advantages over other imaging techniques in assessing tissue perfusion, including the use of microbubbles as blood-pool agents, portability, availability and absence of exposure to radiation or nuclear tracers. Dedicated software packages are necessary to quantify the echo-signal intensity and allow the calculation of the degree of tissue contrast enhancement based on the accurate distinction between microbubble backscatter signals and native tissue background. The measurement of organ transit time after microbubble injection and the analysis of tissue reperfusion kinetics represent the two fundamental methods for the assessment of tissue perfusion by CEUS. Transit time measurement has been shown to be feasible and has started to become accepted as a clinical tool, especially in the liver. The loudness of audio signals from spectral Doppler analysis is used to generate time-intensity curves to follow the wash-in and wash-out of the microbubble bolus. Tissue perfusion may be quantified also by analysing the replenishment kinetics of the volume of microbubbles after their destruction in the imaged slice. This allows to obtain semiquantitative parameters related to local tissue perfusion, especially in the heart, brain, and kidneys.     

Benign focal liver lesions: spectrum of findings on SonoVue-enhanced pulse-inversion ultrasonography

The prevalence of benign focal liver lesions (BFLL) is high both in the general population and in patients with known malignancies. The gray-scale ultrasound (US) technique is usually the first-line imaging modality used in the radiological workup of such lesions, but unfortunately it lacks specificity. Furthermore, Doppler examination may often be unsatisfactory owing to motion artefacts, or when small or deeply located lesions are evaluated. Recently, microbubble-based contrast agents used in combination with gray-scale US techniques, which are very sensitive to nonlinear behavior of microbubbles, have led to a better depiction of both microvasculature and macrovasculature of focal hepatic masses, thus improving the reliability of using US in the assessment of liver tumors. This review illustrates the spectrum of enhancement patterns of BFLL on contrast-enhanced ultrasonography with SonoVue, a second-generation microbubble-based contrast agent.This paper is based on a work accepted for presentation as a scientific paper at the Scientific Assembly and Annual Meeting of the ECR 2004.     

The real capabilities of contrast-enhanced ultrasound in the characterization of solid focal liver lesions

Contrast-enhanced US (CEUS) using intravenous agents is a rapidly evolving field even though the main clinically recognized application is the characterization of focal liver lesions. Several reports have described the improvement provided by CEUS in the characterization of focal liver lesions in comparison to unenhanced US. CEUS with low transmit power insonation allows the real-time assessment of focal liver lesion contrast enhancement and vascularity during the different dynamic phases after injection of an intravenous contrast agent. CEUS allows the accurate characterization of focal liver lesions as benign or malignant based on the lesion contrast enhancement pattern during the arterial phase and lesion vascularity during portal--late phase in comparison to the adjacent liver parenchyma. During the portal--late phase, benign lesions present prevalently a sustained contrast enhancement with hyper or isovascular appearance to the adjacent liver while malignant lesions present prevalently microbubble washout with hypovascular appearance. On the other hand, the histology of focal liver lesions can only be confidently predicted in selected cases by CEUS, as in liver haemangiomas presenting typical nodular peripheral enhancement with subsequent centripetal fill-in and focal nodular hyperplasia with central spoke wheel-shaped contrast enhancement.     

B-mode enhancement at phase-inversion US with air-based microbubble contrast agent: initial experience in humans

Pulse- or phase-inversion ultrasonography (US) sums the signals returned from two 180 degrees ultrasound pulses. Linear scattering from tissue results in a signal void while nonlinear signals from microbubbles stand out. The technique was applied with a US contrast agent in 39 human subjects. B-mode enhancement of vessels and organ parenchyma was seen in all cases. Enhancement occurred from flowing and stationary microbubbles. The flow-independent enhancement of normal and abnormal tissue represents a major advance in contrast material-enhanced US with many potential applications especially in tumor imaging.     

The “humble” bubble: Contrast-enhanced ultrasound

The use of contrast-enhanced ultrasound (CEUS) is increasing within the field of medical imaging. Ultrasonic contrast agent (UCA) contain gas microbubbles similar in size to red corpuscles which provide highly reflective interfaces, enabling dynamic demonstration of echogenic streams of the contrast within the anatomical area of interest on real-time grey scale ultrasound. Longevity of the microbubbles has been improved by changing their composition. The application of CEUS in the UK continues to grow, bringing it into territories historically occupied by computerised tomography (CT) scanning and magnetic resonance imaging (MRI). Hence, the role of CEUS may be of interest to all diagnostic imaging practitioners. Here we summarise the mode of action and use of CEUS, and its role within a range of applications. The potential risks of CEUS are compared to other contrast-enhanced imaging techniques. The benefits of CEUS and its implications for diagnostic imaging practice are also covered.     

Technische Grundlagen der Kontrastsonographie im ��berblick und Ausblick in die Zukunft

Ultrasound contrast agents have considerably expanded the range of ultrasound diagnostics. Up to date ultrasound machines with contrast-specific software allow the selective demonstration and quantification of contrast agents in real-time based on the specific signal signature of oscillating contrast agent microbubbles. After intravenous injection the microbubbles are transported with the bloodstream and distributed purely intravascularly. This allows an artefact-free representation of the vascular architecture and delineation of the vascular lumen, independent of blood flow velocity and with high spatial resolution. Traumatic lesions and active bleeding can be detected with high sensitivity. Blood volume in vessels and organs can be assessed qualitatively and quantitatively. The possibility of short-term destruction of microbubbles within the ultrasound field allows the measurement of blood flow velocity during replenishment and based on that the assessment of perfusion in parenchymal tissue. Target-specific microbubbles for imaging of molecular surface structures as well as drug-loaded microbubbles for local ultrasound-mediated therapy are under development.     

Contrast-enhanced ultrasound: The evolving applications

Contrast-enhanced ultrasound (CEUS) is a major breakthrough for ultrasound imaging in recent years. By using a microbubble contrast agent and contrast-specific imaging software, CEUS is able to depict the micro- and macro-circulation of the targeted organ, which in turn leads to improved performance in diagnosis. Due to the special dual blood supply system in the liver, CEUS is particularly suitable for liver imaging. It is evident that CEUS facilitates improvement for characterization of focal liver lesions (FLLs), detection of liver malignancy, guidance for interventional procedures, and evaluation of treatment response after local therapies. CEUS has been demonstrated to be equal to contrast-enhanced computed tomography or magnetic resonance imaging for the characterization of FLLs. In addition, the applicability of CEUS has expanded to non-liver structures such as gallbladder, bile duct, pancreas, kidney, spleen, breast, thyroid, and prostate. The usefulness of CEUS in these applications is confirmed by extensive literature production. Novel applications include detecting bleeding sites and hematomas in patients with abdominal trauma, guiding percutaneous injection therapy and therefore achieving the goal of using interventional ultrasonography in managing splenic trauma, assessing the activity of Crohn's disease, and detecting suspected endoleaks after endovascular abdominal aneurysm repair. Contrast-enhanced intraoperative ultrasound (US) and intracavitary use of CEUS have been developed and clinically studied. The potential use of CEUS involves sentinel lymph node detection, drug or gene delivery, and molecular imaging. In conclusion, the advent of CEUS has greatly enhanced the usefulness of US and even changed the status of US in clinical practice. The application of CEUS in the clinic is continuously evolving and it is expected that its use will be expanded further in the future.     

The value of ultrasound (US) in the diagnosis of prostate cancer

The value of ultrasound (US) in the diagnosis of prostate cancer has increased in importance in the past decade, which is mainly related due to the increasing incidence of prostate cancer, the most common malignancy in men. The value of conventional gray-scale US for prostate cancer detection has been extensively investigated. The introduction of US contrast agents has dramatically changed the role of US for prostate cancer detection. Advances in US techniques were introduced to further increase the role of US contrast agents. Although most of these advances in US techniques, which use the interaction of the contrast agent with the transmitted US waves are very sensitive for the detection of microbubbles, are mostly unexplored, in particular for prostate applications. First reports of contrast-enhanced US investigations of blood flow of the prostate have shown that contrast-enhanced US adds important information to the conventional US technique. We present a critical evaluation of the current status of transrectal US imaging for prostate cancer detection. Furthermore, we give background information on US contrast agents and imaging modalities. Early results of contrast-enhanced US suggest the feasibility of the use of US contrast agents to enhance US imaging of the prostate. The application of US contrast agents for the detection and clinical staging of prostate cancer is promising. However, future clinical trials will be needed to determine the promise of contrast-enhanced US of the prostate evolves into clinical application.     

Contrast enhanced gray-scale sonography in assessment of joint vascularity in rheumatoid arthritis: results from the IACUS study group

The purpose of this study way to assess the value of contrast enhanced gray-scale ultrasound (CEUS) in detection of vascularity in joints of patients with rheumatoid arthritis (RA) in a multicenter study of the International Arthritis Contrast Ultrasound (IACUS) study group. We assessed 113 joints in 113 patients (44 men, 69 women; mean age 51±14 years) with clinical diagnosis of RA. Gray-scale ultrasound (US), power Doppler US (PDUS) and CEUS, using a low mechanical index US technique, was performed. CEUS was done by bolus administration of the contrast agent SonoVue (Bracco, Milan, Italy) with a dosage of 4.8-ml SonoVue flushed with 10 ml saline. Detection of joint vascularity was performed for differentiation of active synovitis from inactive intra-articular thickening (synovitis/effusion). With the use of US and PDUS, active synovitis could be differentiated from inactive intra-articular thickening in 68/113 joints (60.1%), whereas CEUS enabled differentiation in 110/113 (97.3%) joints (p<0.0001). Thickness measurement of active synovitis was significantly improved after contrast administration (p=0.008). In conclusion, CEUS improves the differentiation of active synovitis from inactive intra-articular thickening. Since CEUS has shown an ability to improve assessment of vascularized synovial proliferation in RA affected joints, this technique may have further potential in monitoring therapy.     

Contrast-enhanced ultrasound for diagnosis of prostate cancer and kidney lesions

PURPOSE OF REVIEW: Conventional ultrasonography of both, kidney and prostate, is limited due to the poor contrast of B-mode imaging for parenchymal disease and limited sensitivity of colour Doppler for the detection of capillaries and deep pedicular vessels. Contrast-enhanced ultrasound (CEUS) overcomes these limitations. RECENT FINDINGS: CEUS investigates the blood flow of the prostate, allows for prostate cancer visualization and for targeted biopsies. Comparisons between systematic and CEUS-targeted biopsies have shown that the targeted approach detects more cancers with a lower number of biopsy cores and with higher Gleason scores compared with the systematic approach. Also the kidney offers promising applications as CEUS improves the detection of abnormal microvascular and macrovascular disorders. SUMMARY: In recent literature CEUS has shown its value for diagnosis of both, prostate cancer and kidney lesions. This paper describes recent improvements and future perspectives of CEUS.     

Abdominal MR: liver and pancreas

Following the introduction of rapid, high-quality scan techniques and the development of new, tissue-specific contrast agents, the applications of MRI for abdominal imaging are experiencing unprecedented growth. This article examines the current status of liver and pancreatic MRI, highlighting technical and methodological approach, use of contrast agents, and main clinical applications. The MRI technique appears to be the ideal diagnostic tool for detection and characterization of benign and malignant liver neoplasms, and for evaluating tumor response after nonsurgical treatments. Dynamic imaging after bolus injection of a gadolinium chelate is currently a fundamental component of an MRI examination of the liver in many instances. Optimal dynamic scanning depends on the use of a multisection spoiled gradient-echo technique that allows one to image the entire region of interest during a single suspended respiration. Images are obtained during four phases relative to the injection of the contrast agent: precontrast, arterial (pre-sinusoidal), portal (sinusoidal), and delayed (extracellular) phase. Liver-specific contrast agents, including hepatobiliary agents and reticuloendothelial system-targeted iron oxide particles, however, may offer advantages over gadolinium chelates in some clinical settings. Computed tomography is still preferred to MRI for imaging the pancreas. However, state-of-the-art MRI may currently be at least as accurate as spiral CT for depiction of inflammatory and neoplastic pancreatic diseases. Moreover, MRI has the advantage of allowing simultaneous investigation of the biliary tree, owing to cholangiopancreatography techniques. Hence, a comprehensive assessment of most pancreatic diseases can be achieved with a single examination.     

Liver investigations: Updating on US technique and contrast-enhanced ultrasound (CEUS)

Over the past few years, the cross sectional imaging techniques (Computed Tomography – CT and Magnetic Resonance – MR) have improved, allowing a more efficient study of focal and diffuse liver diseases. Many papers had been published about the results of a routinely clinical use of the dual source/dual energy CT techniques and the use of hepatobiliary contrast agents in MR liver studies.As a consequence, these new improvements have diverted the attention away from the Ultrasound technique and its technical and conceptual evolutions.In these years of disinterest, US and especially Contrast Enhanced Ultrasound (CEUS) have consolidated and grown in their application in clinical routine for liver pathologies. In particular, thanks to the introduction of new, dedicated software packages, CEUS has allowed not only qualitative, but also quantitative analysis of lesion microcirculation, thus opening a new era in the evaluation of lesion characterization and response to therapy.Moreover, the renewed interest in liver elastography, a baseline ultrasound-based imaging modality, has led to the development of a competitive technique to assess liver stiffness and then for the evaluation of the progression towards cirrhosis, and characterization of focal liver lesions, opening the way to avoid, in selected cases, liver biopsy.The aim of this review is to offer an up-to-date overview on the state of the art of clinical applications of US and CEUS in the study of focal and diffuse liver pathologies. Besides, it aims to highlight the emerging role of perfusion techniques in the assessment of local and systemic treatment response and to show how the liver evolution from steatosis to fibrosis can be revealed by elastography.     

Role for contrast-enhanced ultrasound in assessing complications after kidney transplant

Kidney transplantation (KT) is an effective treatment for end-stage renal disease. Despite their rate has reduced over time, post-transplant complications still represent a major clinical problem because of the associated risk of graft failure and loss. Thus, post-KT complications should be diagnosed and treated promptly. Imaging plays a pivotal role in this setting. Grayscale ultrasound (US) with color Doppler analysis is the first-line imaging modality for assessing complications, although many findings lack specificity. When performed by experienced operators, contrast-enhanced US (CEUS) has been advocated as a safe and fast tool to improve the accuracy of US. Also, when performing CEUS there is potentially no need for further imaging, such as contrast-enhanced computed tomography or magnetic resonance imaging, which are often contraindicated in recipients with impaired renal function. This technique is also portable to patients’ bedside, thus having the potential of maximizing the cost-effectiveness of the whole diagnostic process. Finally, the use of blood-pool contrast agents allows translating information on graft microvasculature into time-intensity curves, and in turn quantitative perfusion indexes. Quantitative analysis is under evaluation as a tool to diagnose rejection or other causes of graft dysfunction. In this paper, we review and illustrate the indications to CEUS in the post-KT setting, as well as the main CEUS findings that can help establishing the diagnosis and planning the most adequate treatment.     

Imaging of carotid arterial diseases with contrast-enhanced ultrasound (CEUS)

Carotid duplex ultrasound is the standard of care for the initial diagnosis of carotid artery bifurcation diseases. But in difficult examinations, carotid abnormalities are commonly encountered and may represent a diagnostic challenge in patients with clinical symptoms as well as in the follow up after carotid endarterectomy or carotid artery stenting. Contrast enhanced ultrasound (CEUS) with low mechanical index (low MI) is a promising new method in the diagnosis and follow up of pathological carotid diseases.Unlike most contrast agents used for magnetic resonance imaging or computed tomography, the microbubbles used in CEUS with SonoVue^® remain within the vascular space and hence can be used to study vascular disease. In addition to improving current carotid structural scans, CEUS has potential to improve or add extra information on carotid arterial diseases.This review describes the current carotid duplex ultrasound examination and compares the pathological findings with CEUS.     

Contrast-enhanced US of hepatocellular carcinoma

PURPOSE: To evaluate the capabilities of contrast-enhanced ultrasound (CEUS) in the characterization of hepatocarcinoma (HCC) in terms of accuracy as compared to spiral CT and diagnostic gain as compared to conventional and Doppler US. MATERIALS AND METHODS: Forty-three patients with viral hepatopathy or cirrhosis diagnosed with HCC (6 histologically and 37 cytologically proven) were retrospectively studied. Between January 2002 and May 2003, all patients were evaluated with CEUS after detection of at least one suspicious nodule on US. CEUS features of HCCs were retrospectively compared with those on conventional and Doppler US, and spiral CT. RESULTS: HCCs varied between 1.2 cm and 18 cm in diameter; 14/43 were small' (< or = 2 cm). In 18/43 patients, HCC was multifocal. Doppler US revealed 24/43 hypervascular nodules. On CEUS, 37/43 (86%) showed contrast enhancement in the arterial phase, 13/37 (35%) with negative colour and power Doppler US examination; in 6/37 (16%) contrast enhancement in the arterial phase was not visible on spiral CT. On CEUS, 6/43 hypovascular HCCs were characterized as malignant in the sinusoidal phase. On CEUS, the sinusoidal phase revealed additional nodules not visible on baseline US in 3/18 multifocal HCCs. CONCLUSIONS: CEUS diagnosis of HCC in cirrhotic liver is possible with a combination of the arterial phase, which shows tumoral hypervascularity in the microcirculation, and the sinusoidal phase, which allows to confirm the malignancy of the nodule.     

Contrast ultrasound in hepatocellular carcinoma at a tertiary liver center: First Indian experience

AIM: To assess the role of contrast enhanced ultrasonography in evaluation of hepatocellular carcinoma (HCC) at the first Indian tertiary liver center. METHODS: Retrospective analysis of contrast enhanced ultrasound (CEUS) examinations over 24 mo for diagnosis, surveillance, characterization and follow up of 50 patients in the context of HCC was performed. The source and indication of referrals, change in referral rate, accuracy and usefulness of CEUS in a tertiary liver center equipped with a 64 slice dual energy computer tomography (CT) and 3 tesla magnetic resonance imaging (MRI) were studied. Sonovue (BR1, Bracco, Italy, a second generation contrast agent) was used for contrast US studies. Contrast enhanced CT/MRI or both were performed in all patients. The findings were taken as a baseline reference and correlation was done with respect to contrast US. Contrast enhanced MRI was performed using hepatocyte specific gadobenate dimeglumine (Gd-BOPTA). Iomeron (400 mg; w/v) was used for dynamic CT examinations. RESULTS: About 20 (40%) of the examinations were referred from clinicians for characterization of a mass from previous imaging. About 15 (30%) were performed for surveillance in chronic liver disease; 5 (10%) examinations were performed for monitoring lesions after radiofrequency ablation (RFA); 3 (6%) were post trans-arterial chemoembolization (TACE) assessments and 3 (6%) were patients with h/o iodinated contrast allergy. About 2(4%) were performed on hemodynamically unstable patients in the intensive care with raised alpha fetoprotein and 2(4%) patients were claustrophobic. The number of patients referred from clinicians steadily increased from 12 in the first 12 mo of the study to 38 in the last 12 mo. CEUS was able to diagnose 88% of positive cases of HCC as per reference standards. In the surveillance group, specificity was 53.3% vs 100% by CT/MRI. Post RFA and TACE specificity of lesion characterization by CEUS was 100% in single/large mass assessment, similar to CT/MRI. For non HCC lesions such as regenerative and dysplastic nodules, the specificity was 50% vs 90% by CT/MRI. The positive role of CEUS in imaging spectrum of HCC included a provisional urgent diagnosis of an incidentally detected mass. It further led to a decrease in time for further management. A confident diagnosis on CEUS was possible in cases of characterization of an indeterminate mass, in situations where the patient was unfit for CT/MRI, was allergic to iodinated contrast or had claustrophobia, etc.CEUS was also cost effective, radiation free and an easy modality for monitoring post RFA or TACE lesions. CONCLUSION: CEUS is a valuable augmentation to the practice of ultrasonography, and an irreplaceable modality for confounding cases and interpretation of indeterminate lesions in imaging of HCC.     

Contrast-specific ultrasound techniques

The advent of microbubble contrast agents has determined an important evolution of ultrasound (US) technology due to the introduction of contrast-specific US techniques. This was due to the fact that neither colour or power Doppler are suitable for correct management of the signals produced by microbubble insonation, as they are limited by the heavy presence of artefacts. Microbubbles may be insonated by a characteristic frequency named resonance or fundamental frequency (f (0)) by using a high or low transmit power. If insonated by a high transmit power, microbubbles produce a wideband harmonic signal due to microbubble destruction. If insonated by a low transmit power, microbubbles produce harmonic frequencies (2f, 3f, 4f) due to their nonlinear physical behaviour. Contrast-specific US techniques have recently undergone an important technical development with the introduction of innovative algorithms able to register selectively the harmonic signals produced by microbubbles and to suppress the signal produced by stationary tissues. The different contrast-specific US techniques may be distinguished by their basic principle into pseudo-Doppler, harmonic, phase-modulation, amplitude-modulation and phase-and amplitude-modulation techniques.     

Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents

Ultrasonography (US) is the first choice for screening patients with suspected liver lesions. However, due to a lack of contrast agents, US used to be less sensitive and specific compared with computed tomography (CT) and magnet resonance imaging (MRI). The advent of microbubble contrast agents increased both sensitivity and specificity dramatically. Rapid developments of the contrast agents as well as of special imaging techniques were made in recent years. Today numerous different US imaging methods exist which based either on Doppler or on harmonic imaging. They are using the particular behaviour of microbubbles in a sound field which varies depending on the energy of insonation (low/high mechanical index, MI) as well as on the properties of the agent themselves. Apart from just blood pool enhancement some agents have a hepatosplenic specific late phase. US imaging during this late phase using relatively high MI in phase inversion mode (harmonic imaging) or stimulated acoustic emission (SAE; Doppler method) markedly improves the detection of focal liver lesions and is also very helpful for lesion characterisation. With regards to detection, contrast enhanced US performs similarly to CT as shown by recent studies. Early results of studies using low MI imaging and the newer perfluor agents are also showing promising results for lesion detection. Low MI imaging with these agents has the advantage of real time imaging and is particularly helpful for characterisation of focal lesions based on their dynamic contrast behaviour. Apart from the techniques which based on the morphology of liver lesions there were some attempts for the detection of occult metastases or micrometastases by means of liver blood flow changes. Also in this field the use of US contrast agents appears to have advantages over formerly used non contrast-enhanced methods although no conclusive results are available yet.     

Nachweis und Charakterisierung von Lebermetastasen

Since the advent of second generation ultrasound (US) contrast agents, ultrasound has caught up with other imaging modalities for the detection and characterization of liver metastases and as a result of its high temporal and spatial resolution it can in some cases even be superior to computed tomography (CT) and magnetic resonance imaging (MRI). Many studies have demonstrated a sensitivity and specificity of over 90%. Due to its high temporal resolution contrast-enhanced US (CEUS) is capable of detecting even a very short duration of hyper-enhancement during the arterial phase. Radiation protection and lack of adverse effects on renal or thyroid function are additional arguments why CEUS should be recommended as the first imaging modality in the evaluation of hepatic metastases in cases of favorable scanning conditions.