contrast-enhanced ultrasound imaging: state of the art · contrast-enhanced ultrasound imaging:...

109©Elsevier & CTSUM. All rights reserved. J Med Ultrasound 2005 • Vol 13 • No 3

R E V I E W

A R T I C L E

Introduction

Contrast enhancement has become a routine part of clinical radiography, computed tomogra-phy (CT), and magnetic resonance imaging (MRI),increasing their diagnostic capabilities. During thelast two decades, contrast-enhanced ultrasoundimaging has been investigated and has graduallyemerged in clinical settings. Concurrent with tech-nological improvements in ultrasound scanningequipment, contrast agents have been developedto meet the demands of this rapidly expandingfield of imaging.

The rapid development of contrast agents forultrasound is precipitated by the performance lim-its of ultrasound imaging and Doppler techniques.As ultrasound is used to study smaller and deeperstructures in the body, the spatial resolution ofgrayscale imaging and Doppler sensitivity becomesimpaired to the degree that it impacts the clinicalutility of ultrasound. Contrast agents promise toimprove the sensitivity and specificity of currentultrasound diagnoses and have the potential toexpand the already broad range of ultrasoundapplications. This article is intended to providean overview of the principles behind ultrasound

Contrast-enhanced Ultrasound Imaging:State of the Art

Ji-Bin Liu*, Gervais Wansaicheong, Daniel A. Merton, Flemming Forsberg, Barry B. Goldberg

The introduction of a variety of ultrasound contrast agents has a significant impact onthe utilization of diagnostic ultrasound in many clinical settings. This article is intendedto provide an overview of the principles behind ultrasound contrast agents along withcontrast-specific imaging techniques and a review of their current and potential clinicalapplications. Ultrasound contrast agents have dramatically improved the sensitivity andspecificity of current ultrasound diagnoses and have the potential of expanding the alreadybroad range of ultrasound applications. Future improvements in imaging techniquescombined with new developments of contrast agents will make ultrasound an even morepowerful diagnostic modality.

KEY WORDS — harmonic imaging, microbubble, tumor diagnosis, ultrasoundcontrast agents, ultrasound imaging technology

■ J Med Ultrasound 2005;13(3):109–126 ■

Jefferson Ultrasound Research and Education Institute, Department of Radiology, Thomas Jefferson University Hospital,Philadelphia, USA.

*Address correspondence to: Dr. Ji-Bin Liu, Jefferson Ultrasound Research and Education Institute, Department of Radiology,Thomas Jefferson University Hospital, 7th Floor Main Building, 132 South 10th Street, Philadelphia, PA 19107, USA.

E-mail: [email protected]

h d d l f f

contrast agents and a review of the clinical appli-cations in which they are useful.

Types of Contrast Agents Available

During the last decade, many new ultrasound con-trast agents have been developed, which are char-acterized by both smaller microbubble mean size(< 10 μm) and prolonged persistence within thecardiovascular circulation (increased from less than1 minute to as much as 10 minutes). Various tech-niques are used to combine materials that controlthe microbubble surface (the encapsulating shell)with gases that inhibit diffusion and microbubbledissolution (air vs. heavy gases such as perfluoro-carbons). At present, several contrast agents havebeen approved for clinical use while others are invarious stages of development (Table).

Basic Principles

Vascular ultrasound contrast agents consist of gas-filled microbubbles stabilized by a thin shell (Fig. 1).They are typically < 8 μm in diameter, which allowsthem to pass through the pulmonary circulation

and systemic capillary beds [1]. When administeredintravenously, ultrasound contrast agents improvethe detection of blood flow and depiction of thevasculature in a variety of structures compared toconventional (i.e. non-contrast) ultrasound due toincreased signal-to-noise ratio (SNR). These agentssignificantly enhance the acoustic backscatter fromblood in both Doppler and grayscale modes, dueto the large impedance difference between the gasand the surrounding blood. Previous techniqueshave used the enhancement of Doppler flow signals(either color Doppler or power Doppler) to visualizethe presence of a contrast agent in the vessels or

J.B. Liu, G. Wansaicheong, D.A. Merton, et al

110 J Med Ultrasound 2005 • Vol 13 • No 3

TTable. fList of ultrasound contrast agents

Name Shell composition Gas Manufacturer

AI-700 Polymer Perfluorocarbon Acusphere

biSphere Gelatin/polymer Air Point Biomedical

BR14 Phospholipid Perfluorobutane Bracco Diagnostics

BY 963 Lipid Air Byk-Gulden

Levovist Galactose/palmitic acid Air Schering

Definity Lipid Perfluoropropane Bristol-Myers Squibb

Imagent Surfactant Perfluorocarbon Imcor Pharmaceuticals

Optison Albumin Perfluoropropane GE Healthcare

Sonazoid Lipid Perfluorobutane GE Healthcare

SonoVue Surfactant SF6 Bracco Diagnostics

MRX-408 Lipid/ligand oligopeptide Perfluoropropane ImaRx

Quantison Albumin Air Andaris Ltd

QFX Albumin Perfluorocarbon Guangzhou Nanfang Hospital

iFig. 1. Microscopic view of microbubbles 2–8 mm in size.

organs of interest. Due to artifacts associated withcolor flow imaging (e.g. color blooming and poorspatial resolution), this may not be an ideal methodof imaging with ultrasound contrast agents. In cer-tain contrast-specific imaging modes, the SNR canbe further improved by suppression of tissue signals.The improved SNR can also be exploited in non-vascular structures like the urinary bladder, fallopiantubes and lymphatic channels.

In order to better separate signals from tissue andthe contrast agent, tissue signal suppression has tobe carried out. This can be achieved by phase/pulsecancellation, coded pulses or amplitude modulation.Although there are different methods commerciallyavailable with differing levels of sophistication andtechnology, grayscale phase/pulse inversion is thebasis of most of the modes used for grayscaleimaging with ultrasound contrast agents [2,3].This technique cancels first harmonic (linearly scat-tered) signals by transmitting a pulse sequencewhere each pulse is an inverted copy of the previ-ous pulse, and then summing the echoes fromsubsequent pulses (resulting in zero under linearscattering conditions). Hence, echoes from station-ary tissue will be suppressed. However, nonlinearechoes arising from contrast microbubbles will notcancel out and, thus, can be preferentially detectedand displayed.

Contrast-specific Imaging Technology

Conventional ultrasound systems have technicallimitations when used with ultrasound contrastagents. These limitations can ultimately reduce theusefulness of the contrast agent effects. Thus, ultra-sound equipment has been and continues to bemodified to optimize their use with a variety of ultra-sound contrast agents.

In general, during insonation, ultrasound contrastagents produce a linear response at low acousticpressures (< 50 kPa), which means the microbub-bles will undergo rhythmic oscillations at a reso-nant frequency (f0ff ). A nonlinear contrast agentresponse occurs at intermediate pressures (from

approximately 50 to 500 kPa). This nonlinearresponse consists of an asymmetric change inmicrobubble size due to greater resistance to com-pression than expansion, which produces harmonicand subharmonic signal components (i.e. frequencycomponents at 2f0ff , 3f0ff , 4f0ff , etc., and at 1/2f0,ff , 1/3f0ff ,etc.) (Fig. 2) [4]. Eventually, at higher acousticpressures (> 500 kPa; although these pressure levelsvary significantly from agent to agent), the contrastmicrobubbles will be disrupted and destroyed.

Harmonic Imaging

Harmonic imaging (HI) is one such modificationwhich was originally developed for contrast-enhanced ultrasound imaging. The phenomenon ofharmonic generation is not confined to microbubble-based contrast agents but can also be induced innative tissue, and this forms the basis of native tis-sue harmonic imaging (THI). HI uses the samebroadband transducers used for conventional imag-ing, but the ultrasound system is configured to pri-marily receive echoes at the second harmonicfrequency (i.e. twice the transmit frequency). HIprovides a way to better differentiate areas with andwithout contrast microbubbles. Therefore, contrast-enhanced HI has the potential to demonstrate, inreal-time, grayscale blood flow imaging (i.e. perfu-sion imaging) (Fig. 3). The frequencies and para-meters of wideband HI that are used depend on

Contrast-enhanced Ultrasound

111J Med Ultrasound 2005 • Vol 13 • No 3

iFig. 2. f b bbl h h f dSpectrum of a microbubble agent showing the funda-mental (f =ff d2 MHz), second harmonic (HI at 4 MHz), andssubharmonic (SHI at 1 MHz) components.

the specific characteristics (i.e. microbubble size andshell composition) of the ultrasound contrast agentbeing utilized. Selection of the appropriate agentand imaging mode allows optimization of the util-ity of contrast-enhanced ultrasound imaging [5].

Initially, HI relied on simple filtering techniquesto extract the harmonic microbubble signals, butmore sophisticated processing schemes haveemerged over the recent years. Currently, themode with the best SNR and suppression ofunwanted tissue signal is wideband HI. Furtherimprovements are possible with the use of pulseinversion HI [6–8]. Additional details on the equip-ment and software available for ultrasound con-trast imaging may be found in the recent EFSUMBguideline paper [9].

Intermittent Imaging

In order to enhance detection of tumor neovas-cularity with contrast agents, these agents musttraverse into these smaller vessels. Conventionalultrasound systems, however, often deliver powerlevels that are sufficient to destroy contrast micro-bubbles, especially when using a high mechanicalindex (MI). If the microbubbles are destroyedbefore they reach the neovasculature, the desired

enhancement of flow in tumor vessels will not beobserved. A potential solution to this problem isthe use of intermittent ultrasound imaging, whichhas been shown to increase ultrasound contrastenhancement [10–12]. The degree of enhance-ment with intermittent imaging is dependent uponflow rate, acoustic power output and the frequencyof insonation [13]. With continuous grayscaleultrasound imaging, contrast microbubbles withinthe imaging plane may be destroyed during theacquisition of each frame of the image. Since atypical grayscale ultrasound image is refreshed at30 frames per second, the available contrast agentfor each new image frame is that amount whichenters the imaging plane in 1/30th of a second. Inthis short time between frames, contrast may enterlarger vessels, but will not generally reach the micro-circulation. With intermittent imaging, the ultra-sound beam is turned off for longer periods betweeneach image frame. More contrast microbubbles thenenter the imaging field during this interscanperiod, resulting in increased echo-enhancement.Furthermore, the contrast material will have timeto traverse further into the capillary bed.

Flash echo imaging is a particular combinationof regular and intermittent grayscale imaging tech-niques, consisting of low power real-time monitorpulses transmitted continuously, while microbubble



BA

iFig. 3. rCompared with fundamental imaging (A), second harmonic imaging (B) of a kidney after contrast injections shows betterenhancement and vascular definition.

destruction is achieved with intermittent higherpower flash pulses [14]. These two modes are dis-played simultaneously in a dual screen format. Eachsequence of multiple-frame (1–15 frames) flashpulses can be triggered manually or electronically(e.g. every 1–8 seconds). The principle of micro-bubble destruction in intermittent mode has beenused by investigators to measure mean myocardialmicrobubble velocity and to assess the microvas-cular cross-sectional area during constant infusion ofcontrast [15]. The product of these two estimatesis the mean myocardial blood flow (i.e. a measureof myocardial perfusion). To date, flash echo imag-ing is the only quantitative method for ultrasoundperfusion estimation (in mL/min/g) that has beendeveloped.

Continuous Imaging

Although intermittent imaging can obtain highcontrast within a single frame, this imaging modeis not real-time, which may impair the visualizationof some structures and the utility of the modality.In the last few years, a number of other methodshave been introduced (some commercially), such aspulse inversion HI, superharmonic imaging, powerharmonics, coded harmonic angio and agent detec-tion imaging [16–21], which employ low acousticpower settings and contrast-specific processing toproduce a real-time display of the region of interest.The visualization of the enhancement pattern ofthe normal and abnormal tissues can significantlyimprove the diagnostic capability of ultrasoundimaging.

Other Imaging Methods

When imaging small vessels or if the concentration ofcontrast is low, the echogenicity of contrast micro-bubbles can be limited. However, collecting imagesover an extended period of time (e.g. 3–10 sec-onds) using alternative post-processing techniques(e.g. maximum intensity projection) can achieve a

temporally summed (or compounded) enhancedimage. This is the basis of a commercially availabletechnique [3], which has currently been imple-mented by three manufacturers (Fig. 4).

Under specific conditions, gas microbubbles gen-erate subharmonics, which occur mainly at half thetransmitted frequency. Compared to superharmonicimaging, an advantage of subharmonic imaging isthat tissue signal is minimal, which results in a highagent-to-tissue ratio (i.e. high SNR). Reports havedescribed the feasibility and implementation ofsubharmonic ultrasound imaging [22,23] (Fig. 5).Currently, subharmonic ultrasound imaging is still inits early development.



iFig. 4. Contrast-enhanced imaging using micro-flow imagingContrast-enhanced imaging using micro-flow imagingdmode shows a high resolution depiction of normally perfused

kidney parenchyma in an animal model.

iFig. 5. Subharmonic image of a canine kidney shows the per-fusion pattern of vasculature of the kidney with suppression offusion pattern of vasculature of the kidney with suppression ofbackground tissue.

Clinical Applications

Clinical applications for ultrasound contrast agentscan potentially be found in any structure that is eval-uated with conventional ultrasound, with the onlyexception being the fetus. The major applications ofultrasound contrast agents are in cardiac and hepaticimaging. Other applications are being explored,although there are currently fewer reports on theirclinical use. The assessment of vascularity by demon-stration of microvessels or increased parenchymalsignal intensity provides a new parameter in diag-nostic evaluation, just like intravenous contrast hasenhanced CT and MRI as well as nuclear imaging.

Hepatic usesThe use of ultrasound contrast agents for evalua-tion of the liver has become widespread and canbe considered routine in parts of Europe and Asia[4]. Current microbubble-based agents are essen-tially blood pool agents. The type of enhancementdemonstrated in the liver is similar to that shown

with contrast-enhanced CT and MRI. Therefore,interpretation of the enhancement patterns incontrast-enhanced ultrasound is similar to thoseperformed with contrast-enhanced CT or MRI. Inaddition, continuous scanning at low acoustic pres-sures may reveal dynamic contrast enhancementthat can be quite helpful for characterization of avariety of focal liver lesions (Fig. 6).

Hepatic pathology can be considered in twomain groups: focal lesions and diffuse disease. Thecharacteristic patterns of enhancement in benignand malignant liver lesions have been described [24].There is good concordance with the enhancementcharacteristics of focal liver lesions using contrast-enhanced ultrasound with those that have beendescribed for CT and MRI studies [25,26]. This is truefor benign and malignant hepatic tumors [27]. Thereis better characterization of certain focal lesionslike hepatocellular carcinoma (HCC) and metastaticlesions (Fig. 7) compared to an unenhanced ultra-sound scan [28]. This is especially the case for small(< 2 cm) focal liver lesions. Contrast agents have



A B

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iFig. 6. r (A) Baseline imaging shows a heterogeneous livermass (T). (B) Following a bolus injection of Sonovue (Bracco,

tMilan, Italy), characteristic peripheral globular enhancementof the tumor (T) is present. (C) After several minutes, cen-

ttripetal filling of the tumor (T) is observed. This enhancementppattern is consistent with a hemangioma.

been shown to be useful in improving the detec-tion of HCC (Fig. 8), in differentiating HCC fromregenerating nodules and to detect recurrence intreated lesions. Complementary information maybe obtained when compared to contrast-enhancedCT scans [29]. This improvement shows good inter-observer concordance [30]. Focal nodular hyper-plasia has a central star-like pattern of enhancementthat can be observed with continuous contrast-enhanced ultrasound (Fig. 9) [31]. Due to the tran-sient nature of enhancement, the star-like patternmay not be seen in all examinations, especially ifan intermittent mode is used.

In some cases, there is overlap of the benignand malignant features in focal liver lesions on

contrast-enhanced ultrasound, but the use of addi-tional parameters may provide advantages overCT and MRI. For example, hepatic transit time hasbeen found to be useful in monitoring postradiofrequency (RF) ablation procedures [32] andcontrast-enhanced power Doppler imaging forradiotherapy [33]. For diffuse liver disease like cir-rhosis, global parameters such as hepatic transittime show promise in being able to diagnose cir-rhosis without biopsy. A prospective study thatassessed the diagnostic accuracy of transhepaticcirculatory time with an ultrasound contrast agentdemonstrated that the hepatic artery to hepaticvein and portal vein to hepatic vein interval timeswere significantly shorter in the cirrhosis group



A B

iFig. 7. (A) Conventional grayscale imaging shows suspicious masses within a heterogeneous liver in a patient with colon cancer.(B) Contrast-enhanced pulse inversion harmonic imaging improved the delineation of multilobulated tumors (T) within theenhanced liver parenchyma.

A B

iFig. 8. t(A) Harmonic imaging of a hepatocellular carcinoma demonstrates tumor (T) enhancement in its arterial phase using AgentDetection Imaging mode (ADI; Siemens, Issaquah, WA, USA). (B) In its delayed phase, the tumor (T) appears as a hypoechoic lesionwithin the contrast-enhanced parenchyma.

(7.4 ± 1.7 s and 1.9 ± 1.5 s, respectively) comparedwith those in the noncirrhosis group (normal: 15.6 ±2.1 s and 11.1 ± 1.7 s, p < 0.001 and p < 0.001; andhepatitis: 12.8 ± 4.1 s and 7.8 ± 4.4 s, p < 0.001and p < 0.002, respectively) [34]. Hepatic transittime can also distinguish between cirrhosis andsevere hepatitis from mild hepatitis, although thereis overlap between severe hepatitis and cirrhosis.

Interventional and intraoperative usesThe ablation of lesions with RF is a technique thatis increasing in popularity, especially in the treat-ment of unresectable liver lesions. The ideal methodof monitoring ablation during the procedure itselfand in post-ablation follow-up has not been estab-lished. Contrast-enhanced ultrasound has been usedin diagnosis of lesions before ablation as well asmonitoring the outcome of ablation procedures inthe liver (Fig. 10) [35].

Contrast-enhanced ultrasound has the potentialto be very useful as it allows real-time assessmentof lesion vascularity [36] and is similar to dynamicCT in its sensitivity and specificity [37,38]. Grayscalepulse inversion HI is superior to power Dopplercontrast-enhanced ultrasound [39], and both aresuperior to conventional ultrasound [40] in demon-strating residual tumor after thermal ablation. Similarfindings have been described in a preliminaryreport on ablation of renal lesions [41]. The use of

contrast-enhanced ultrasound for intraoperativeevaluation of focal liver lesions should promise toimprove detection of sub-centimeter nodules, shownodular vascularity with greater detail, and poten-tially improve clinical outcomes [42].

Contrast-enhanced ultrasound imaging has beenused to delineate thermal lesions from viable tissueduring RF ablation of the prostate in an animalmodel. The initial results demonstrated that contrast-enhanced imaging is able to guide and monitor theRF ablation of the entire prostate (Fig. 11). This tech-nique holds a great potential for future use in humansas an innovative treatment of prostate cancer [43].



A B

iFig. 9. (A) Conventional grayscale imaging shows an isoechoic lesion (T) in the right lobe of the liver. (B) After a bolus injection of tcontrastffagent, the tumor demonstrates a central star-like pattern of enhancement, consistent with a diagnosis of focal nodular hyperplasia.

iFig. 10. rPulse inversion harmonic imaging of a liver tumorpost radiofrequency ablation demonstrates a small residualpost radiofrequency ablation demonstrates a small residualviable nodule (arrows) at the periphery of the lesion.

Echocardiographic usesIn the United States and Europe, the Food and DrugAdministration (FDA) and the European Unionhave approved several contrast agents for use duringechocardiography examinations with the specificindication of providing ventricular opacificationand enhancement of endocardial border definitionin patients with technically suboptimal echocar-diograms (Fig. 12). Contrast echocardiographyincludes applications for the right ventricle such asdemonstration of shunts, abnormalities in the posi-tion or presence of the great vessels, and for the leftventricle such as cardiac structure, valvular functionand wall motion. Additional applications includeperfusion quantification and reperfusion assessmentof the myocardium [44,45].

The administration of contrast agents has beenshown to enable more accurate measurement ofleft ventricular volume, ejection fraction, diagnosisand grading of valvular disease, intracardiac throm-bus detection, aortic dissection, detection of compli-cations of myocardial infarction (such as ventricularrupture and aneurysm formation), and improvedassessment of systolic function compared to con-ventional ultrasound imaging. In stress echocar-diography, contrast agents increase the number ofinterpretable segments, which allows accurate assess-ment of left ventricular function [46]. At the myocar-dial level, contrast agents can be used to diagnose



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iFig. 11. c(A) Contrast-enhanced pulse inversion harmonicimaging of a canine prostate after radiofrequency ablationidentifies a demarcated thermal lesion (L) within contrast-perfused normal parenchyma. This information is useful forperfused normal parenchyma. This information is useful formonitoring radiofrequency ablation of the entire prostate. (B) Pathologic specimen showing the coagulated lesion corre-ssponding to the ultrasound findings.

A B

iFig. 12. (A) Suboptimal echocardiography of the left ventricle (LV) shows inadequate endocardial border definition. (B) After intra-venous contrast injection, complete opacification of the left ventricle (LV) is obtained and the endocardial borders are clearly seen.lrl

infarction and assess tissue viability. Coronary arterystenoses can be localized and their severity quantifiedusing contrast-enhanced intermittent HI. Coronaryperfusion rates may be calculated using microbub-ble destruction and reperfusion techniques [47].

Cerebrovascular usesSignificant limitations exist in current transcranialDoppler ultrasound examinations. These include lowreproducibility, inter-investigator variability, andinadequate access through the skull. Thus, transcra-nial Doppler examinations can be improved with theuse of ultrasound contrast agents [48]. Ultrasoundcontrast agents provide better delineation of normalblood flow, occlusions, pseudo-occlusions, stenoses,and collaterals in the extracranial and intracranialvascular beds [49]. For examination of the extracra-nial carotid arteries, contrast administration canincrease visualization of the residual lumen, increasediagnostic confidence, and decrease the number ofindeterminate examinations. However, the appli-cations of contrast agents to the carotid artery are intheir infancy. Clinical trials are necessary to deter-mine optimal techniques for contrast-assisted carotidimaging.

Thyroid and parathyroid usesUltrasound contrast agents have been used to obtaintime-intensity curves of flow through thyroid nod-ules. This has the potential to differentiate betweenbenign and malignant lesions and to characterizehypovascularized malignant nodules that could notbe observed without contrast [50]. A more rapidtime to peak signal intensity has been documentedin malignant thyroid nodules [51]. In parathyroidlesions that do not show flow with conventionalultrasound, contrast agents can provide useful infor-mation by visualizing typical color Doppler signalsof the parathyroid lesions. This can help to distin-guish parathyroid nodules from thyroid lesions [52].

Gastrointestinal usesContrast-enhanced ultrasound has been used toevaluate patients with portal hypertension byenhancing the Doppler signal and permitting

better visualization of esophageal varices transab-dominally [53] and perforating veins in recurrentvarices [54]. This technique has great potential forimproving early detection of visceral varices andmonitoring of therapeutic response.

Bowel pathology may be diagnosed on thebasis of altered vascularity. Ultrasound contrastagent can demonstrate ischemia [55] and help dif-ferentiate benign from malignant gastrointestinalstromal tumors [56]. Assessment of inflammatorybowel disease can also be improved with the useof contrast agents by demonstrating increasedvascularity in affected segments [57]. This is ofbenefit in determining if active disease is presentor only fibrosis even when the bowel wall does notshow significant thickening [58]. The same reason-ing applies in the evaluation of pathologic hyper-emic bowel, e.g. in acute appendicitis [59].

The use of orally administered ultrasound con-trast agents for bowel evaluation has also beenshown to be of value [60]. Oral contrast agentsappear to significantly improve the ability toimage both normal and abnormal structures in thegastrointestinal tract (Figs. 13 and 14), and to pro-vide an acoustic window for evaluation of adjacentorgans such as the pancreas (Fig. 15). Acousticartifacts associated with bowel gas often preventcomplete ultrasonic evaluation of the pancreas,



iFig. 13. dFollowing the ingestion of oral contrast, ultrasoundimaging shows a uniform and homogeneous echogenicity withinthe stomach (ST). Note that a demarcated defect on the poste-rior wall of the stomach is clearly seen, which corresponds to anulceration lesion.

which has led to CT being the primary choice forthe evaluation of this organ. Evaluation of oralultrasound contrast agents has shown significantimprovement in visualization of the stomach, pan-creas and adjacent structures. These oral agentscould be coupled in the future with an intravenouscontrast agent, enhancing the ability of ultrasoundto detect pancreatic tumors.

Gallbladder and biliary tree usesThere are a few published reports that describe theuse of ultrasound contrast agents for the evaluationof abnormalities of the gallbladder and biliary tree.

One report described how the detection and stagingof malignant hilar obstructions of the biliary treewas improved by the use of Levovist in the post-vascular phase of sonography compared with con-ventional sonography [61]. Some studies describedhow ultrasound contrast agents can increase visual-ization of the vasculature in the gallbladder wall andhyperemia of the liver parenchyma adjacent to thegallbladder in cases of acute cholecystitis [62,63].

Renal usesContrast-enhanced ultrasound of the kidney canprovide a clear and detailed view of renal vascular-ity, with early enhancement in the arterial phasefollowed by an intense and uniform enhancementin the renal cortex (i.e. perfusion imaging). Theenhancement then extends to the pyramids untilthey become isoechoic with the cortex.

The application of ultrasound contrast agentsin the characterization of renal tumors has greatpromise. Contrast-enhanced ultrasound has thepotential to perform dynamic time-contrast inten-sity curves [64], characterize focal renal lesions [65],evaluate for the presence of a pseudocapsule inrenal cell carcinoma [66], and evaluate the collectingsystem for vesicoureteric reflux [67]. Other potentialrenal applications for contrast imaging include theevaluation of renal perfusion, kidney transplants,and monitoring tumor ablation procedures.



iFig. 14. Transverse ultrasound imaging of the stomach (ST)after ingestion of oral contrast shows irregular thickening of the

twalls of the pylorus with a narrowed gastric cavity, consistentwith gastric cancer in the pyloric region.

A B

iFig. 15. (A) Pre-contrast transverse imaging of the mid epigastrium reveals partial obscuration of the head of the pancreas. (B) Post-contrast imaging shows a hypoechoic mass (M) at the head of the pancreas through a contrast-filled stomach (ST).Dilation of the pancreatic duct is also seen.

Prostate usesIn order to more accurately detect the presence ofprostate cancer, researchers have focused upon thedetection of neovascularity in prostate cancer. Thevascular supply to malignant prostate tissue differsfrom the vascularity of normal prostate tissue in den-sity and distribution of microvessels. Studies of theprostate demonstrate a clear association of increasedmicrovessel density with the presence of cancer [68].Quantitative assessment of microvascular densitymay actually provide important data to guide ther-apeutic decisions [69]. Unfortunately, the microves-sels that proliferate around and within prostatecancers are below the limits of the resolution ofconventional Doppler ultrasound.

One potential solution to this problem maybe the use of ultrasound contrast agents to detect flow in microvessels associated with cancer.An early study suggested that contrast-enhancedcolor flow detection of increased vascularity wasassociated with the presence of prostate cancer[70]. Several additional studies have demonstrated

Doppler enhancement of vessels in prostate cancer[71,72]. These preliminary studies suggested thatcontrast agents might be useful in ultrasoundevaluation of prostate vascularity and improvethe detection of cancer (Fig. 16). Both contrast-enhanced color Doppler and harmonic grayscaleimaging have been used successfully to improveimaging of prostate cancer and to guide targetedbiopsy for definitive diagnosis of prostate cancer[73–77].

Pancreatic usesThe pancreas may be evaluated with contrast-enhanced ultrasound via a transabdominal approachor endoscopically [78]. Preliminary reports show that contrast-enhanced ultrasound improves the con-spicuity of pancreatic carcinoma compared to con-ventional ultrasound [79,80]. Quantitative analysis ofthe amount of post-contrast enhancement may beuseful in separating benign and malignant pancreaticlesions [81]. Further work is needed to validate theseearly findings.



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iFig. 16. (A) Baseline conventional ultrasound imaging of thepprostate reveals no evidence of abnormality. (B) Contrast-enhanced real-time pulse inversion harmonic imaging shows anenhanced focal area (M) compared with the rest of the gland.(C) With intermittent imaging mode, the enhanced area is moredramatically seen. Pathology proved this hypervascular area tobe prostate cancer.

l h f l

Vascular usesPreliminary reports have described how contrast-enhanced ultrasound of the renal arteries canimprove visualization of the renal arteries and itsbranches, improve the detection of renal arterystenosis, reduce the duration of an examinationand improve the accuracy of these examinations[82,83]. Improved detection of intra- and extrarenalarteries with contrast-enhanced color Dopplerimaging provides a superior roadmap of the vesselsthemselves and allows for more accurate placementof the spectral Doppler sample volume. Severalclinical contrast studies in the evaluation of renalartery stenosis (RAS) have produced encouragingresults [82,83]. In a multicenter trial, 191 patientsreferred for renal arteriography were examinedwith contrast-enhanced ultrasound. The ability toimage the renal arteries improved from 75% to 90%after contrast administration (p < 0.001). Accuracyin diagnosing RAS > 50% increased from 65% onnon-contrast evaluations to 78% with the use ofcontrast [84,85].

Trauma usesTraumatic lesions have common enhancementfeatures on cross-sectional imaging, independentof the organ and tissues involved. The arterial treeis invariably involved in all organs and contrast-enhanced ultrasound easily detects parenchymallesions, such as lacerations and hematomas, pro-viding detailed information on them [86]. Thefindings were consistent with those of CT exams,suggesting that contrast-enhanced ultrasound couldbe a reliable technique for the evaluation of post-traumatic parenchymal damage.

In the evaluation of trauma to the abdomen,contrast-enhanced ultrasound has the advantage ofdemonstrating viable tissue and improving contrastbetween traumatic lesions and remaining normalparenchyma. Although superior to conventionalultrasound [87], contrast-enhanced ultrasound isnot yet a replacement for contrast-enhanced CT[88]. However, contrast-enhanced ultrasound hasseveral advantages over CT, including the ability tobe performed at bed-side within the intensive care

unit and to be used for serial evaluations to deter-mine if active bleeding is present. Thus, additionalresearch in this area is warranted.

Lymphatic usesMicrobubble-based ultrasound contrast agentshave been injected subcutaneously to enhancedetection of lymphatic channels (LCs) and sentinellymph nodes (SLNs) [89,90]. Clinically, SLN map-ping is important for tumor staging (such asbreast, skin, and gastrointestinal tumors) and todetermine the use of adjuvant therapies. With traditional methods (e.g. lymphoscintigraphy orinjection of blue dyes and surgical dissection), it isimpossible to demonstrate the internal architectureof the SLN, which is important for the detection ofmetastatic spread to SLNs (initial accuracy 86%).Contrast-enhanced lymphosonography is a mini-mally-invasive technique to localize draining LCsand SLNs (Fig. 17) and has the ability to evaluateSLNs for metastases (Fig. 18). This new techniquealso has the potential to enhance ultrasound-guidedbiopsies of SLNs for improved tissue sampling fordefinitive pathologic assessments.

Gene and Drug Delivery andTargeted Agents

Functional ultrasound imaging of specific tissuesusing targeted microbubbles represents a newapproach that departs from the concept that



iFig. 17. Following subcutaneous injection of contrast agent inan animal model, pulse inversion harmonic imaging identifies a

lcontrast-filled lymphatic channel (LC; arrows) and its sentinellymph node (SLN).

microbubbles passively transit the microcirculationlike red blood cells. Targeted ultrasound imaginginvolves the design and synthesis of microbubblesthat will adhere to endothelium or other targetsunder disease-specific conditions (e.g. inflamma-tion). To the extent that the microbubbles aredesigned to adhere to molecular epitopes on thesurface of abnormal endothelium, targeted con-trast imaging could provide capabilities for in vivoultrasonic detection of phenotypic features ofendothelium that predate clinical disease and/orare otherwise not detectable using currently avail-able technologies [91–93]. Investigators havedemonstrated that microbubbles can be phagocy-tosed intact by activated neutrophils and mono-cytes and can be detected by ultrasound imaging.These findings indicate that contrast-enhancedultrasound may provide a useful means for thenoninvasive assessment of inflammation and tofollow the response to treatment [94].

Targeted imaging using contrast microbubbleshas advantages over other molecular imagingmethods. Unlike nuclear imaging approaches, ultra-sound contrast microbubbles stay within the vas-cular space and have a short circulation time. Thisis useful to the extent that the technique is notsusceptible to nonspecific signals resulting fromextravasation of the imaging agent or retention innon-target organs such as the liver. However, thesefeatures are intrinsically limited to the interrogation

of phenomena occurring on the surface of endothe-lial cells, thus excluding its application to manyimportant physiologic processes that occur intracel-lularly and outside of the vascular space, for example,gene therapy. Recent reports of acoustically activenanoparticle emulsions (or gas-filled nanobubbles)capable of exiting the vascular space may offer anexciting solution to this challenge [95].

Targeted microbubbles may ultimately haveutility beyond their diagnostic attributes. Ultrasonicdestruction of microbubbles appears to enhancedelivery of genes, drugs, and lysis of clots (Fig. 19)[96,97]. The ability to target therapeutics by design-ing the delivery agent (microbubble) to be ableto reach the site of interest may ultimately proveto be another powerful clinical application of thisexciting technology.

Summary

In conclusion, present and future ultrasound con-trast agents should provide for increased diagnos-tic capabilities in a variety of normal and abnormalvascular applications. These agents will enhancetumor vascularity, delineate areas of ischemia, andimprove visualization of many abnormalities, includ-ing the detection and characterization of tumors insuch organs as the liver. Ultrasound contrast agentsthat are non-toxic, intravenously injectable, and



iFig. 18. In a swine melanoma model, contrast-enhanced ultra-ssound imaging identifies a metastatic sentinel lymph node (N),which appears as partially enhanced normal lymphatic tissueand hypoechoic tumor deposits (T). iFig. 19. rDiagram showing a targeted contrast agent used for

thrombolysis.

stable for recirculation are already being used rou-tinely in a variety of clinical applications. Futuredevelopments including the continued modifica-tion of ultrasound equipment to better exploit theenhancement properties of contrast agents shouldincrease the capability of these agents to improvethe sensitivity and specificity of ultrasound imag-ing. The field of targeted ultrasound imaging is stillin its infancy, and as with the field of molecularimaging in general, much remains to be done todevelop this area into a clinical reality.

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