28 Guidelines

Guidelines and Good Clinical Practice Recommenda-

tions for Contrast Enhanced Ultrasound (CEUS) –
Update 2008

EFSUMB study group M. Claudon1, D. Cosgrove2, T. Albrecht3, L. Bolondi4, M. Bosio5, F. Calliada6, J.-M. Correas7, K. Darge8, C. Dietrich9,
M. D'On ofrio10, D. H. Evans11, C. Filice12, L. Greiner13, K. Jäger14, N. de. Jong15, E. Leen16, R. Lencioni17, D. Lindsell18,
A. Martegani19, S. Meairs20, C. Nolsøe21, F. Piscaglia22, P. Ricci23, G. Seidel24, B. Skjoldbye25, L. Solbiati26, L. Thorelius27,
F. Tranquart28, H. P. Weskott29, T. Whittingham30

Affiliations Affiliation addresses are listed at the end of the article.

Key words Thematic groups composition has also been published in French [1] and Chi-
●
" contrast agent
! nese [2]. Time has however moved on, and EF-
●
" liver
SUMB and the group of experts who developed
●
" urinary
Chairpersons these first guidelines took the view in 2006
●
" v. ureteric reflux

●
" pancreas Introduction D. H. Evans that they should be revisited and expanded to
●
" trauma 1 General considerations include recommendations for applications in
●
" transcranial US
2 Liver the kidney, in vesico-ureteric reflux, in the pan-
2.1 Characterisation of focal liver E. Leen creas, in trauma and in the cerebral circulation.
lesion In order to facilitate the production of these
2.2 Detection of focal liver lesion T. Albrecht new guidelines and recommendations a further
2.3 Monitoring of ablative L. Solbiati two meetings of experts were held, the first in
treatment
Bologna in September 2006 in conjunction with
3 Kidney Hp. Weskott
the EUROSON/SIUMB meeting, the second im-
4 Reflux K. Darge
mediately following the European Symposium
5 Pancreas M. D' Onofrio
6 Blunt abdominal trauma L. Thorelius
on Ultrasonic Contrast Agent Imaging in Rotter-
7 Transcranial US S. Meairs dam in January 2007.
8 Technical appendices C. Nolsøe As previously these guidelines are based on
comprehensive literature surveys including re-
sults from prospective clinical trials. On issues
Ultrasound (US) contrast agents (UCAs), in con- where no significant study data were available,
junction with contrast specific imaging techni- evidence was obtained from expert committee
ques, are increasingly accepted in clinical use reports or was based on the actual consensus
for diagnostic imaging and post-interventional of experts in the field of US and contrast en-
workup in several organs. To those not intimate- hanced Ultrasound (CEUS) during the consen-
ly involved in the field, the rapid advances in sus conferences. During the meeting of experts
technology and techniques can be difficult to in Rotterdam many additional new and exciting
received 7.12.2007 follow. In March of 2003, at the EUROSON Con- developments were discussed, and whilst some
accepted 10.12.2007 gress in Copenhagen, it was agreed that it would are quickly entering clinical practice, it was felt
Bibliography be useful to produce a document providing a too early to include them in the current recom-
DOI 10.1055/s-2007-963785 description of essential technical requirements, mendations.
Published online 2008 proposed investigator qualifications, suggested These guidelines and recommendations provide
Ultraschall in Med 2008; 29: study procedures and steps, guidance on image general advice for the use of UCAs. They are in-
28 – 44 © Georg Thieme Verlag interpretation, recommended and established tended to create standard protocols for the use
KG Stuttgart · New York ·
clinical indications and safety considerations. and administration of UCAs and improve the
ISSN 0172-4614
Initially a set of guidelines for the use of ultra- management of patients. Individual cases must
Correspondence sonic contrast agents in the liver alone were be managed on the basis of all clinical data
Prof. Michel CLAUDON developed. These were presented and discussed available for that specific case. This second ver-
Department of Radiology, CHU in detail at an EFSUMB special consensus meet- sion will be subject to change to reflect future
de Nancy Brabois
ing held in Rotterdam in January 2004. The re- advances in scientific knowledge and the rapid-
Allée du Morvan
54511 Vandoeuvre les
sulting consensus document was published in ly evolving field of US technology.
Tel.: ++ 33/3/83 15 41 83 the August 2004 edition of Ultraschall in der
Fax: ++ 33/3/83 15 35 23 Medizin/European Journal of Ultrasound, and
m.claudon@chu-nancy.fr

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
 Guidelines 29

1 General Considerations flow. While conventional ultrasound can detect high concentra-
! tions of microbubbles, in practice their assessment usually re-
1.1 Introduction quires contrast-specific imaging modes.
The development of ultrasound contrast agents (UCAs), which Contrast specific US modes are generally based on the cancella-
perform as blood pool tracers, have overcome the limitations tion and/or separation of linear US signals from tissue and uti-
of conventional B-Mode and colour or power Doppler US and lization of the nonlinear response from microbubbles [9 – 12].
enable the display of parenchymal microvasculature [3 – 5]. De- Non-linear response from microbubbles is based on two differ-
pendent on the contrast agent and the US-mode, the dynamic ent mechanisms:
lesion enhancement pattern is visualized during intermittent 왘 non-linear response from microbubble oscillations at low
or continuous imaging. Enhancement patterns are described acoustic pressure, chosen to minimize disruption of the mi-
during subsequent vascular phases (e. g. arterial, portal-venous crobubbles,
and late phase for liver lesions), similar to contrast enhanced 왘 high energy broadband non-linear response arising from mi-
computer tomography (CECT) and/or contrast enhanced mag- crobubble disruption.
netic resonance imaging (CEMRI). Contrast enhanced ultra- Non-linear harmonic US signals may arise also in tissues them-
sound (CEUS) and CECT or CEMRI are not equivalent as UCAs selves due to a distortion of the sound wave during its propa-
have different pharmacokinetics and are confined to the intra- gation through the tissue. The extent of this harmonic response
vascular space, whereas the majority of currently approved from tissue at a given frequency increases with the acoustic
contrast agents for CT and MRI are rapidly cleared from the pressure, which is proportional to the mechanical index (MI).
blood pool into the extracellular space. Low solubility gas UCAs (e. g. SonoVue®, Optison®, Luminity®)
An inherent advantage of CEUS is the possibility to assess the are characterized by the combination of improved stability with
contrast enhancement patterns in real time with a substantial- favorable resonance behavior at low acoustic pressure. This al-
ly higher temporal resolution than other imaging modalities, lows minimally disruptive contrast specific imaging at low MI
without the need to predefine scan-timepoints or to perform and enables effective investigations over several minutes with
bolus-tracking. Furthermore, administration can be repeated the visualization of the dynamic enhancement pattern in real
due to the excellent patient tolerance of UCAs. time.
In addition to intravenous (IV) use, UCA intracavity applications Low MI techniques furthermore lead to effective tissue signal
such as intravesical administration can be performed. suppression, as the non-linear response from the tissue is mini-
UCA studies are subject to the same limitations as other types of mal when low acoustic pressures are used [9, 12, 13].
ultrasound: as a general rule, if the baseline ultrasound is very US imaging with air filled microbubbles (e. g. Levovist®) at high
suboptimal, CEUS may be disappointing. pressure is dependent on microbubble disruption which is a sig-
nificant limitation for real time imaging.
1.2 Commercially Available Ultrasound Contrast Agents
in Europe 1.3.2 Intracavitary administration of UCAs
Four transpulmonary UCAs are currently approved and marke- In addition to intravenous use, UCAs are suitable for intracavi-
ted within European Countries: tary administration, particularly for performing contrast-en-
왘 Levovist® (air with a galactose and palmitic acid as a surfac- hanced voiding urosonography (VUS) [14 – 16]. After intravesi-
tant) (Schering, introduced in 1996). Main indications include cal administration UCAs markedly enhance the US backscatter
heart, abdomen, vesico-ureteric reflux and transcranial. of bladder content. Consequently, refluxing microbubbles in
왘 Optison® (octafluoropropane (perflutren) with an albumin the ureter and pelvicalyceal system and flow in the urethra
shell) (GE Healthcare, introduced in 1998). Sole indication is are easily visualized. Levovist® has been approved for this in-
to date cardiac. dication in children in a number of countries. A few clinical
왘 SonoVue® (sulfur hexafluoride with a phospholipid shell)(- studies using SonoVue® for sonographic reflux examination
Bracco, introduced in 2001). Approved indications are cardiac have been published recently [17 – 20].
(endocardial border delineation), macrovascular (cerebral
and peripheral arteries, portal vein) and microvascular (char- 1.3.3 Assessment of Anti-angiogenic Treatment
acterisation of focal lesions in liver and breast). Since anti-angiogenic treatment very frequently induce lesion
왘 Luminity® (octafluoropropane perflutren with a lipid shell) necrosis with no change in the volume of the initial tumor, new
(Bristol-Myers Squibb, introduced in 2006). Sole indication functional imaging technologies are particularly suitable for the
to date is cardiac. early assessment of the response to treatment [21], a task for
The composition, packaging, storage, indications and contrain- which the RECIST and WHO size criteria [22, 23] appear inap-
dications of these agents are detailed in appendix 1. propriate. Studies of various types of tumor treated with targe-
There are other UCAs approved outside Europe or under inves- ted therapies have recently confirmed that the use of microbub-
tigation. ble contrast agents enable early prediction of the response to
treatment, demonstrating changes in tumor parenchymal perfu-
1.3 Imaging Techniques using Ultrasound Contrast sion and emergence of necrosis with no change in tumor volume
Agents [24, 25]. Early detection of the emergence of secondary resis-
1.3.1 Background on UCAs and contrast specific modes tance could also be demonstrated 6 to 9 months prior to the in-
The UCAs which are currently used in diagnostic US are charac- crease in lesion bulk, thus providing an opportunity for rapid ad-
terized by a microbubble structure consisting of gas bubbles sta- justment of the therapeutic strategy [26].
bilized by a shell [3, 4, 6 – 8]. UCAs act as blood pool agents. They
strongly increase the US backscatter and therefore are useful in 1.3.4 Equipment and Technical Requirements
the enhancement of echogenicity for the assessment of blood See systems specification in appendix 2.

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
30 Guidelines

1.4 Investigator Training Users should balance the potential clinical benefit from the use
The EFSUMB minimal training requirements for the practice of UCAs against the theoretical possibility of associated adverse
of medical ultrasound in Europe define three levels of training bioeffects in humans.
requirements [27]. It is likely that most CEUS examinations Some general recommendations are:
would be performed by level 2 or 3 investigators. Specific 왘 Resuscitation facilities should be available.
minimum training recommendations will be developed for 왘 Caution should be considered for off label use of UCAs in tis-
the use of UCAs. sues where damage to microvasculature could have serious
It is recommended that investigators wishing to undertake clinical implications, such as in the eye, the brain and the
CEUS examinations should gain experience by observing con- neonate.
trast studies being performed by experts in this field. They 왘 As in all diagnostic ultrasound procedures, the operator
should also ensure that their equipment is optimised for con- should be mindful of the desirability of keeping the displayed
trast examination by discussion with their equipment manu- MI and Thermal index (TI) low, and of avoiding unduly long
facturers. It is also important that in their own department exposure times.
there are sufficient numbers of examinations being performed 왘 Caution should be exercised when using UCAs in patients
and different types of pathological processes being observed with severe coronary artery disease.
to acquire and maintain their skills. 왘 The use of contrast agents should be avoided 24 hrs prior to
Practitioners need to be competent in the administration of con- extra-corporeal shock wave therapy.
trast agents, familiar with any contra-indications and be able to
deal with any possible adverse effects within the medical and le-
gal framework of their country. 2 Liver
!
1.5 Safety Considerations Focal liver diseases have evolved into the single most important
In general, UCAs are very safe with a low incidence of side ef- application of CEUS (setting aside the applications in echocar-
fects. They are not nephrotoxic and do not interact with the diography) because of the marked improvement over conven-
thyroid and therefore it is not necessary to perform laboratory tional ultrasound in both their detection and characterisation.
tests of renal function before administering them. UCAs are Subject to some limitations that are detailed in the following
not licensed in pregnancy and breastfeeding is a contra-indi- sections, CEUS now equals CECT and in some instances exceeds
cation in some countries. it in accuracy. Partly this is because of the real-time nature of
The incidence of severe hypersensitivity or allergic events is modern contrast ultrasound which reveals important rapid
lower than current X-ray and comparable to MR contrast agents. flow phenomena; CT, with its intermittent imaging, sometimes
Life threatening anaphylactoid reactions in abdominal applica- misses these. Partly also the persistence of microbubbles be-
tions have been reported with a rate of 0.001 % [28]. Investiga- yond the large vessel enhancement period (the late phase) pro-
tors, therefore, should take the necessary precautions. vides a marker for the sinusoidal space; lesions that lack this
A few fatal events in critically ill patients who have undergone vascular space, notably metastases, appear as late phase de-
also contrast enhanced echocardiographic examinations have fects.
been reported. Contraindications for the use of Sonovue® were Thus the late phase is mainly used for detection of malignancies
defined with the EMEA in 2004. In October 2007, the Food and and the arterial phase mainly for characterising focal liver le-
Drug Administration issued a warning which cautions the use of sions. In this section, characterisation is covered first, followed
Definity® and Optison® in patients with severe cardiopulmonary by detection. While this may seem illogical, it reflects the order
disease (FDA Alert 10/ 2007): the basis of this alert is currently of usage dictated by the liver's haemodynamics.
under evaluation by the scientific and clinical communities, as
well as other regulatory agencies, as of December 2007. 2.1 Characterisation of focal liver lesions (FLL)
In echocardiographic applications, premature ventricular con- 2.1.1 Background
tractions have been described when high MI ultrasound and Due to the dual blood supply of liver tissue by the hepatic artery
end-systolic triggering have been used together [29, 30], and (25 – 30%) and the portal vein (70 – 75 %), three overlapping vas-
the release of subclinical myocardial bio-markers has been re- cular phases can be defined and visualized using contrast en-
ported in high MI clinical studies [31]. hanced sonography. Depending on individual circulatory status,
There is a theoretical possibility that the interaction of diag- enhancement resulting exclusively from the hepatic artery sup-
nostic ultrasound and UCAs could produce bioeffects. In vitro ply usually starts from 10 – 20 seconds post-injection into a per-
cellular effects that have been observed include sonoporation, ipheral vein and lasts for approximately 10 – 15 seconds. This is
haemolysis and cell death. Although observed in vitro, such followed by the portal venous phase, which usually lasts until 2
bioeffects may have relevance for the in vivo situation as they minutes after UCA injection. The late phase lasts until the clear-
result from interactions between single gas bodies and single ance of the US contrast agent from the hepatic parenchyma, up
cells. Data from small animal models suggest that microvascu- to approximately 4 – 6 minutes post injection for SonoVue®. This
lar rupture could occur when microbubbles are insonated. This late phase differs from the equilibrium phase of extracellular CT
might be a potential safety issue in special situations where and MRI agents. The origin of this late phase is subject of ongo-
such vascular damage would be clinically important such as ing scientific discussion; suggested mechanisms include sinu-
ocular and brain US. soid pooling and RES/Kupffer cells uptake [32, 33] (● " Table 1).

The MI provides a useful, albeit very rough, on-screen indica- The arterial phase provides information on the degree and pat-
tor of the potential for non-thermal effects. The potential for tern of vascularity. The portal and late phases provide informa-
non-thermal bioeffects exists in all modes, including conven- tion about the wash out of UCA from the lesion compared to nor-
tional 2D imaging and 3D methods. mal liver tissue.

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
 Guidelines 31

Table 1 Vascular Phases in Contrast Enhanced Ultrasound of the Liver. The 2.1.2.2 High Mechanical Index (MI) Techniques
individual global haemodynamic situation in a given patient will influence the High MI techniques in which microbubbles are deliberately de-
time of onset of the three vascular phase times stroyed, have been initially used for characterisation of FLLs.
visualization When required, intermittent scanning of the lesion is performed
post-injection time (seconds) during all 3 phases. Such high MI techniques are no longer re-
commended.
phase start end
arterial 10 – 20 25 – 35
portal-venous (PV) 30 – 45 120 2.1.3 Image Interpretation and Evaluation (Enhancement
late > 120 bubble disappearance Patterns of FLL)
(approx. 240 – 360) 2.1.3.1 Benign Lesions
Sustained enhancement in the portal-late phase characterizes
most benign solid liver lesions. They can be further character-
Portal and late phase enhancement can provide important infor- ized by enhancement patterns during the arterial phase: e. g.
mation regarding the character of the lesion: most malignant le- enhancement of the whole lesion (typical of focal nodular hy-
sions are hypo-enhancing while the majority of solid benign le- perplasia [FNH]) or initial peripheral globular-nodular enhance-
sions are iso- or hyper-enhancing [34 – 59]. ment (haemangioma).
The typical enhancement patterns are summarized in ● " Table 2

2.1.2 Study Procedure for the following lesions: haemangioma, FNH, focal fatty spar-
2.1.2.1Low Mechanical Index (MI) Techniques ing, focal fatty change, regenerative nodule, simple cyst, adeno-
Low MI contrast specific techniques allow dynamic imaging ma, abscess.
with subsequent evaluation of the three different vascular pha-
ses using a low solubility gas UCAs. 2.1.3.2 Malignant Lesions
The steps recommended in the study procedure are as follows: Hypoenhancement of solid lesions (darker than the surround-
왘 Baseline investigation in B-Mode, potentially including Dop- ing liver) in the late phase characterizes malignancies: all me-
pler techniques. tastases show this feature and no exception has been reported
왘 After identification of the target lesion(s) the transducer is to date. A typical HCC is characterized by arterial phase hyper-
kept in a stable position while the imaging mode is changed vascularity and wash-out in the late phase. Atypical variations
to low MI contrast specific imaging. occur, especially in well-differentiated tumours, as are descri-
왘 Using low MI contrast specific imaging modes, it is crucial to bed in the table. The arterial phase is important for demonstrat-
provide sufficient tissue cancellation with maintenance of ing hypervascularity of HCC and of hypervascular metastases.
adequate depth penetration (a function of MI and gain, both Bland (blood) thrombus is usually avascular, though when well
of which must be adjusted). Adequate cancellation of tissue organised, venous recanalisation channels may form. Since
signals is characterized by disappearance of the B-Mode par- they are formed of at least partly viable tumour tissue, tumour
enchymal liver structures. Major vascular structures and thrombus in the portal or hepatic veins contains malignant
some anatomical landmarks such as the diaphragm remain neovascularity which can be demonstrated with CEUS. The en-
barely visible. hancement patterns are different (a tumour blush rather than
왘 UCA is administered as a bolus injection followed by a 5 – discrete vessels) and the arterial signals in tumour can be con-
10 ml saline flush. It is adviced to use a needle diameter of at firmed on contrast enhanced spectral Doppler [60]. A marked
least 20 Gauge whenever possible to avoid loss of bubbles wash out in the portal and late phases may occur in metastat-
due to mechanical impact during injection. The needle dia- ic portal vein thrombosis, up to anechoic appearance, resem-
meter should not be smaller than 20 Gauge to avoid loss of bling bland thrombus in this vascular phase [61].
bubbles due to mechanical impact during injection. A stop The enhancement patterns used for the characterization of ma-
clock should be started at time of UCA injection. lignant lesions (HCC, hypovascular Mets, hypervascular Mets,
왘 Because of the dynamic nature of real time CEUS, it is recom- cholangiocarcinomas) are summarized in ● " Table 3.

mended to document the investigation on video or digital

media (essential clips for each vascular phase should be 2.1.4 Recommended Uses and Indications
stored). CEUS should be performed and interpreted with knowledge of
왘 Note: In some contrast specific US modes a simultaneous dis- clinical and laboratory data. With typical enhancement pat-
play of tissue and contrast signals has been implemented. terns on CEUS and in an appropriate clinical setting, charac-
This modality is particularly useful for small lesions to ensure terization of haemangioma, focal nodular hyperplasia, metas-
that the target lesion is kept within the scanning field during tasis and HCCs can be obtained at a high level of probability
CEUS. and confidence. Focal liver lesions with atypical enhancement
왘 A single bolus is usually adequate, but further injections can patterns or technical suboptimal studies require further inves-
be used if the examination after the first bolus was inconclu- tigation.
sive.
왘 Continuous scanning for 60 – 90 seconds is recommended to 2.1.4.1 Recommended Indications
continuously assess the arterial and portal-venous phase. For CEUS is indicated in the following clinical situations (●
" Fig. 1a,

assessment of the late phase scanning may be used intermit- b):

tently until the disappearance of the UCA from the liver mi- 왘 Incidental findings on routine US.
crovasculature has been observed. 왘 Lesions or suspected lesion in chronic hepatitis or liver cir-
rhosis.

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
32 Guidelines

Table 2 Enhancement (E) patterns of benign focal liver lesions

tumor entity arterial phase PV phase late phase

haemangioma
typical features peripheral-nodular E, no central E partial/complete centripetal filling complete E.
additional features small lesion: complete, rapid centripetal E non-enhancing areas
rim enhancement
FNH
typical features hyper-enhancing, complete, early hyper-enhancing iso/hyper-enhancing
additional features spoke-wheel arteries, centrifugal filling hypo-enhancing central scar hypo-enhancing central scar
feeding artery
focal fatty sparing
typical features iso-enhancing iso-enhancing iso-enhancing
focal fatty change
typical features iso-enhancing iso-enhancing iso-enhancing
regenerating nodule
typical features iso-enhancing iso-enhancing iso-enhancing
other features hypo-enhancing
simple cyst
typical features non-enhancing non-enhancing non-enhancing
adenoma
typical features hyper-enhancing, complete iso-enhancing iso/hypo
additional features non-enhancing areas hyper-enhancing
non-enhancing areas non-enhancing areas
abscess
typical features rim E, no central E hyper/iso-enhancing rim, no central E hypo-enhancing rim, no central E
additional features enhanced septa hypo-enhancing rim
hyper-enhanced liver segment enhanced septa
hyper-enhanced liver segment

Table 3 Enhancement patterns of malignant focal liver lesions

tumour entity arterial phase PV phase delayed phase

HCC
typical features (in cirrhosis) hyper-enhancing, complete iso-enhancing hypo/iso-enhancing
non-enhancing areas non-enhancing areas
additional features basket pattern/chaotic vessels
enhancing tumor thrombus in PV and/or HV
atypical features non-enhancing lesion non-enhancing lesion non-enhancing lesion
HCC in non cirrhotic liver hyper-enhancing hypo/non enhancing hypo/non enhancing
hypovascular mets
typical features rim E hypo-enhancing hypo/non enhancing
additional features complete E non-enhancing areas
non-enhancing areas
hypervascular mets
typical features hyper-enhancing, complete hypo-enhancing hypo/non enhancing
additional features chaotic vessels
cystic metastasis
typical features hyper-enhancing nodular/rim component hypo-enhancing hypo-enhancing
cholangiocarcinoma
typical features rim E hypo/non enhancing hypo/non enhancing
additional features non-enhancing

왘 Lesions or suspected lesion in patient with a known history of 2.2 Detection of focal liver lesions
malignancy. 2.2.1 Background
왘 Patient with inconclusive MRI/CT or cytology/histology re- Conventional US is the most frequently used imaging procedure
sults. for the primary diagnosis of abdominal organs and the liver, but
왘 Characterization of portal vein thrombosis. is less accurate in detection and staging of liver lesions than con-
trast-enhanced CT and MRI or intraoperative US. The main rea-
2.1.4.2 Limitations sons for this are problems in the detection of small sized and/or
왘 Specificity and sensitivity are markedly reduced in attenuat- isoechoic lesions, especially for deep lesions or in difficult anato-
ing livers and for deep-sited lesions. mical areas (e. g. in the subdiaphragmatic areas).

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
 Guidelines 33

a
Late Phase:
Sustained Enhancement

Yes: Benign No: Malignant

Arterial Phase:
Arterial Phase: Arterial Phase:
Hypo-E Arterial Phase: Arterial Phase: Arterial Phase: Arterial Phase:
Hyper-E Hyper/Iso-E
Peripheral Nodular Iso-E Hypo-E "Rim" Hyper-E "Basket" Hypo-E
Diffuse Centrifugal Diffuse Centripetal
Pattern Progressive DiffusePattern Enhancement Pattern / Diffuse Pattern Variable Pattern
Pattern Pattern
Centripetal

Focal Haemangioma Adenoma Focal Metastasis Hepatocellular Cholangiocarcinoma

Nodular Fatty Change Carcinoma
Hyperplasia

b
Arterial Phase:
Hyper-E

Yes No

Portal / Late Phase: Portal / Late Phase:

Portal / Late Phase: Portal / Late Phase: Portal / Late Phase:
Wash-out to Peripheral Nodular
Loss of Hyper-E Iso-E Slight Hypo-E
Pronounced Hypo-E Centripetal Filling-in

Indeterminate / HCC
Indeterminate /
HCC* RN vs. DN Metastasis Haemangioma
Highly Suspicious HCC
vs. Atypical HCC Cholangiocarcinoma

Fig. 1 a Characterisation Algorithm for FLL in Non-Cirrhotic Liver. b Char- hypervascularisation and subsequent wash out by CT/MR is requested to
acterisation Algorithm for FLL in Cirrhotic Liver.The diagnostic of HCC for establish the diagnostic of HCC in FLL 1 – 2 cm detected during surveil-
lesions > 2 cm, newly emerged during surveillance in cirrhosis, can be es- lance, or in FLL > 2 cm emerged out of surveillance programs. HCC = Hepa-
tablished on CEUS alone. In addition to CEUS, a confirmation of arterial tocellular Carcinoma; DN = Dysplastic Nodule; RN = Regenerative Nodule.

Based on the published literature [62 – 64] there is clear evi- 왘 Using low MI contrast-specific imaging modes, it is crucial to
dence that CEUS improves detection of metastases compared provide sufficient tissue cancellation with maintenance of
to conventional US. Some studies have shown that the accura- adequate depth penetration (a function of MI and gain, both
cy in the detection of liver metastases is comparable to CECT of which must be adjusted). Adequate cancellation of tissue
[65, 66] provided scanning conditions allow a complete inves- signals is characterized by disappearance of the B-Mode par-
tigation of all liver segments. Cholangiocarcinomas behave in enchymal liver structures. Major vascular structures and
the same way as hypovascular metastases and are well shown some anatomical landmarks such as the diaphragm remain
as late phase defects, even when they are not visualised on barely visible.
baseline ultrasound [56]. 왘 UCA is administered as a bolus injection followed by a 5 –
It has also been shown that CEUS can detect metastases not visi- 10 ml saline flush. The needle diameter should not be smaller
ble on CT [63, 65, 67, 68]. On the other hand, CEUS can also miss than 20 Gauge to avoid loss of bubbles due to mechanical im-
lesions shown on CT. The overall performance of both modalities pact during injection. A stop clock should be started at time of
is comparable. UCA injection.
Recent studies have shown that the addition of USCA improves 왘 Because of the dynamic nature of real time CEUS, it is recom-
the sensitivity and specificity of intraoperative US [69, 70] Con- mended that the investigation is to be documented on video
trast enhanced Intraoperative US (IOUS) is emerging as the new or digital media (essential clips for each vascular phase
reference method for liver imaging in selected cases. should be stored).
왘 Note: In some contrast-specific US modes a simultaneous dis-
2.2.2 Study Procedures play of tissue and contrast signals has been implemented to
2.2.2.1 Low Mechanical Index (MI) Techniques ensure that a lesion seen on CEUS can be concurrently de-
The steps recommended in the study procedure are as follows: tailed on convention B-mode.
왘 Baseline investigation in B-Mode, potentially including Dop- 왘 A single bolus is usually adequate, but further injections can
pler techniques. be used if the examination after the first bolus was inconclu-
왘 Change to low MI contrast specific imaging mode. sive.

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
34 Guidelines

왘 Complete examination of the liver using various sweeps is 왘 In selected cases, when clinically relevant for treatment plan-
possible within a time frame of approximately 4 – 5 min in- ning, to assess the number and location of liver metastases as
cluding all vascular phases. a complement to CECT and/or CEMRI.
왘 Scan in sweeps to cover the whole liver. The left lateral decu- 왘 Surveillance of oncology patients where CEUS has previously
bitus and sometimes the standing position improve liver cov- been useful.
erage. 왘 Suspected cholangiocarcinoma where other imaging is incon-
왘 For detection of hypovascular metastasis, the benefit of scan- clusive or not scheduled.
ning before 90sec is debatable and some experts would avoid 왘 Suspected liver trauma in some situations (see section 6.3 for
scanning before this time. On the other hand, if a lesion is details).
visible on the baseline scan, this lesion should be scanned
during the arterial and portal phase for characterisation (in 2.2.4.2 Limitations
addition to detection of other lesions) (for details see under 왘 Although often readily shown, very small metastases ( < 5 –
2.1.2 Characterisation, Investigation procedure). 10 mm) may be overlooked as they may be too small to pro-
duce visible defects in the portal and late phases.
2.2.2.2 High Mechanical Index (MI) Techniques 왘 Subdiaphragmatic lesions, especially those in segment 8, may
Due to the difficult examination technique, the routine use of not be accessible to conventional or contrast enhanced US. In-
high MI techniques and Levovist is no longer recommended. tercostal scanning and positioning the patient in the left de-
cubitus position can help reduce this limitation.
2.2.3 Image Interpretation 왘 Since CEUS has limited penetration, especially in the case of
2.2.3.1 Metastases hepatic steatosis or cirrhosis, deep-sited lesions may not be
In the portal-venous and the late phase, metastases show as accessible. Scanning in the left lateral decubitus position
hypo-enhancing defects and these phases are the most useful brings the liver forward and closer to the transducer and can
time to detect them. In comparison, most benign lesions show help overcome this limitation and should be part of the rou-
uptake at this time and are therefore not likely to be confused tine survey.
with metastases. 왘 The falciform ligament and surrounding fat can cause an en-
The appearance of metastases in the arterial phase is variable. hancement defect that may be confused as a metastasis.
Hypovascular metastases show in CEUS as hypoechoic lesions 왘 A potential pitfall is that small cysts, which were undetected
with or without an additional rim enhancement, while hyper- on unenhanced US are sometimes detected on late phase
vascular metastases show as brightly enhancing hyperechoic scanning. These can often be distinguished from metastases
lesions. as they characteristically show increased through transmis-
sion on CEUS. Careful re-evaluation with conventional US
2.2.3.2 HCC may help to show the cystic nature of these lesions.
Detection of HCCs, especially in the cirrhotic liver, may be dif-
ficult. They may be visualised as areas of increased enhance- 2.3 Monitoring of Local Ablative Treatment
ment in the arterial phase, but the short duration of this phase 2.3.1 Background
can make full surveillance of the whole liver impossible. The Percutaneous ablation therapies play a key role in the manage-
late phase appearances are variable, as previously described, ment of patients with liver malignancies, both HCC and metas-
but in a proportion of patients, HCCs are well shown as relative tases [71 – 77].
defects at this time and this can facilitate detection. There is Diagnostic imaging in patients undergoing local ablative treat-
currently no data to support the routine use of USCA in the de- ment includes US, CECT and/or CEMRI during pretreatment di-
tection of HCC. (For characterisation of indeterminate lesions agnostic work-up and at distinct time points within the follow-
in cirrhotic livers, see above.) up of the patient (usually within the first week post treatment
and after 1, 3, 6 etc. months).
2.2.3.3 Inflammatory mass and abscess Unenhanced US, even when combined with color/power Dop-
Inflammatory masses and abscesses usually show arterial phase pler, does not provide any reliable information about the out-
enhancement, which is rim-like in abscesses. Thereafter they come of ablation treatments. The assessment of vascularization
wash out to appear as relative defects on late phase imaging. and tissue perfusion is crucial to differentiate necrosis from re-
Detection and size assessment are thereby improved. sidual viable tumor. Biphasic helical CT or dynamic gadolinium-
enhanced MRI can predict the extent of the coagulation area to
2.2.3.4 Trauma within 2 – 3 mm.
Traumatic liver lacerations and haematomas are well demon- When US is used as the imaging modality for guiding ablations,
strated in all phases as non-enhancing defects. The same meth- the addition of UCA can provide important information in each
od is of value in other solid organs such as the spleen and kid- of the following procedural steps [78 – 85]:
ney (for details see section 6 on trauma). 왘 pre-treatment assessment of lesion vascularity in order to
compare pre- and post-ablation patterns at the end of abla-
2.2.4 Recommended Uses and Indications tion and for better delineation of lesions poorly visualized
2.2.4.1 Recommended Indications on baseline US scans,
왘 All liver ultrasound scans to “rule out” liver metastases or ab- 왘 guidance of the ablation needle/probe into lesions not visua-
scess, unless conventional ultrasound shows clear evidence lized or not well delineated with unenhanced US,
of these lesions. 왘 immediate assessment of the therapeutic result to detect re-
sidual viable tumour areas,
왘 post-ablation follow-up to assess treatment response.

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
 Guidelines 35

2.3.2 Study Procedures lite nodules around small HCCs (5 – 10 mm range of distance
2.3.2.1 Pre-treatment Contrast-Enhanced Ultrasound from the main tumor [88]), it is strongly recommended to as-
왘 For procedure, refer to 2.2. sess the presence and thickness of the “safety margin” follow-
왘 Accurate pre-treatment size assessment (measurement of the ing ablation not only for liver metastases but also for HCCs.
three largest diameters in two orthogonal scan planes) of ev- In the early (e. g., within the first 30 days) post-ablative evalua-
ery mass to be treated is mandatory. Either real-time volu- tion using CEUS, a thin and uniform enhancing rim can be visi-
metric (4 D) studies or post-processing volume reconstruc- ble along the periphery of the necrotic area, similar to findings
tions for volume calculation of every target are highly on CECT. Misinterpretation of this perilesional hyperemic halo
recommended. This enables accurate treatment planning: as residual viable tumour can be avoided by comparing post-ab-
number of needle/probe insertions needed to thoroughly lation images with pre-ablation scans.
treat each tumor mass, path of every insertion and in case of
large tumors, modality of overlapping contiguous ablation 2.3.4 Recommended Uses and Indications
volumes [86, 87]. This procedure is to be performed under 왘 As a complement to CECT and/or CEMRI for pretreatment sta-
CEUS imaging only when CEUS and conventional US provide ging and assessment of target lesion vascularity. Pretreat-
significantly different identifications of the mass borders. ment optimized CECT and/or CEMRI are recommended.
Field depth, selected scan plane, acoustic gain and mechani- 왘 Facilitation of needle positioning in cases of incomplete or
cal Index (MI) (or acoustic power) used for the pre-treatment poor lesion delineation on unenhanced US.
CEUS study of each lesion must be pre-defined. 왘 Evaluation of immediate treatment effect after ablation and
왘 Images and/or movie clips are to be video- or digitally stored guidance for immediate re-treatment of residual unablated
for precise comparison with immediate post-ablation stu- tumoral areas.
dies. 왘 Assessment of tumour recurrence, when follow-up CECT or
CEMRI are contraindicated or not conclusive. Although CECT
2.3.2.2 Positioning of probe/needle (only when the lesion is and/or CEMRI are considered to be the standard techniques
not visible on unenhanced US). for assessment of treatment outcome, CEUS may be used in
왘 For procedure, refer to 2.2. the follow-up protocols.
왘 Probe/needle is inserted during the vascular phase in which
the target is optimally depicted.
왘 Periprocedural Assessment of Treatment Response (for ther- 3 Kidney
mal ablation). !
왘 Unenhanced US is used to monitor the reduction of the hyper- In most centres, ultrasound is the preferred first imaging modal-
echoic “cloud” due to gas formation caused by ablation. This ity in patients with known or suspected renal disease. Main ob-
usually requires 5 –15 minutes. jectives are to measure renal size, to prove or rule out focal le-
왘 For procedure, refer to 2.2. sions, to detect obstruction of the collecting system and to look
왘 For each treated lesion, the same system settings and scan for vascular disorders by means of Doppler techniques [89]. Of-
planes must be used as for the pre-ablation assessment. ten unexpected findings like anatomic variations or focal lesions
왘 Images and/or movie clips are to be digitally stored for com- are detected and need further clarification.
parison with previously stored pre-ablation images. The differentiation between simple cyst and solid or complex
왘 If additional probe/needle insertions are performed, repeated tumour can often be made by greyscale US. However, acoustic
doses of UCA can be given. properties do not contribute in distinguishing between differ-
ent types of tissue and therefore benign and malignant lesions
2.3.2.3 Follow-up Investigation to Assess Tumor recurrence may be difficult to distinguish. Pulse wave and color Doppler
왘 See procedure described at 2.2. techniques help to characterize renal blood flow, with limita-
tion because of attenuation, lack of sensitivity, blooming, and
2.3.3 Image Interpretation – Definition of Complete angle dependency. A benefit from using CEUS can therefore be
Treatment Response expected [90].
The most important imaging finding that indicates complete ab- The following recommendations deal with the uses of ultra-
lation is the disappearance of any previously visualized intrale- sound contrast agents for the evaluation of the micro- and mac-
sional enhancement on contrast-enhanced images. This must be rovasculature of the kidneys, including the characterization of
assessed throughout the whole volume of each tumor which has focal renal lesions, the detection of lesions and the monitoring
undergone ablation. The size of the post-treatment avascular vo- of local treatment. The use of CEUS in this indication has not yet
lume of the necrosis achieved should be compared with the size obtained regulatory appoval and thus represents an off-label
of pre-treatment volume of tumor(s). The simultaneous display use, which should be justified by an individual risk/benefit as-
of tissue and contrast signals, available on some equipment, is of sessment for the respective patient, based on the available sci-
particular value for short and long term follow up of treated le- entific data.
sions, to ascertain whether persistent enhancing portions of tis-
sue are inside or outside the ablated lesion. 3.1 Characterization of Focal Renal Lesions
In hypoenhancing lesions (e. g. most liver metastases), comple- 3.1.1 Background
teness of treatment can be assessed by comparing the pre-treat- The kidneys receive 20 – 25 % of the cardiac output. The renal
ment lesion volume and location with the volume and location cortex tissue receives 90% and the medulla the remaining 10%.
of the post-treatment coagulated or necrotic region. This also Medullary blood flow is slower than cortical flow.
determines whether if a sufficient perilesional “safety” margin Unlike CECT or CEMRI, CEUS may be performed in patients
has been achieved. Due to the reported high incidence of satel- with impaired renal function or uretric obstruction that may

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
36 Guidelines

be contraindications to performing contrast CT or Gadolinium 3.1.2.2 High Mechanical Index (MI) Techniques
enhanced MR examinations. UCAs have no reported clinical Due to the difficult examination technique, the routine use of
side effects on the kidneys in humans to date. Two contrast high MI techniques is no longer recommended.
boluses are usually necessary in order to examine both kid-
neys. Although several papers describe the use of Levovist® 3.1.3 Image interpretation and evaluation
with intermittent imaging, today most centres use low solubi- 3.1.3.1 Benign and malignant renal lesions
lity gas agents such as SonoVue® with real time, low MI ima- Dinstinguishing between developmental anomalies (eg septa of
ging. Bertin) and neoplasm can be helped by a contrast study: the hae-
As UCAs are confined to the vascular bed, CEUS can not provide modynamics of pseudotumours are identical to the remainder of
information about the excretory function of the kidneys. The the kidney whereas true tumours usually show spatial or tem-
wash in phase can be divided into a short cortical enhancement poral differences from normal tissue.
phase, beginning 10 to 15 seconds after bolus injection, fol- So far there are no reliable criteria to distinguish malignant from
lowed by a medullary enhancement phase which progresses benign tissue, for example renal cell carcinoma from renal me-
much more slowly via the vasa recta, and proresses from the tastasis, angiomyolipoma, oncocytoma and leiomyoma. There-
outer to the inner portion of the medulla. The duration of par- fore, the value of CEUS in distinguishing different solid tumour
enchymal enhancement depends on the vascular status and entities is limited [91].
age of the patient, renal blood flow and the sensitivity of the Some CEUS findings may be of clinical benefit in the work up of
US device used. Because of the high perfusion in the cortex, renal tumours. The proof of vascularization by showing tissue
high microbubble concentration in the superficial parenchyma enhancement can demonstrate that the tissue is viable. This
may cause attenuation in deeper portions of the kidney. This finding may be useful in evaluating echoic material within the
can be avoided by reducing the dose of contrast agent. In slim, collecting system or the urinary bladder, or in differentiating
easy to scan patients with superficial kidneys the dose may be benign thrombus from venous tumor extension into the renal
reduced to 1 – 1.5 ml of contrast agent. The wash out phase is vein or the vena cava.
first recognized by a decrease in medullary enhancement, fol- As in hepatic abscess, renal abscess shows an early rim en-
lowed by a slower cortical wash out. hancement and quicker wash out compared to normal renal
cortex. Usually the pararenal tissue appears hypervascularized
3.1.2 Study Procedure [92].
3.1.2.1 Low Mechanical Index (MI) Techniques
Low MI contrast specific techniques allow dynamic imaging 3.1.3.2 Complex cystic lesions
with evaluation of the different vascular phases using a low Complex cysts, which are classified as type 2F, 3 or 4 accord-
solubility gas UCAs. ing to the Bosniak classification [93], are probably the best in-
The steps recommended in the study procedure are as follows: dication for renal CEUS [94]. So called complex cysts, a term
왘 Baseline investigation in B-Mode, potentially including Dop- adapted from CT and MR, are characterized by a thickened or
pler techniques. irregular wall, calcifications, septa or solid components. UCA
왘 After identification of the target lesion(s) the transducer is helps to characterize these lesions by demonstrating vascular-
kept in a stable position while the imaging mode is changed ization which suggests that the lesion is malignant. Therefore,
to low MI contrast specific imaging. For comparison, both CEUS may help in characterizing lesions in which CT and/or
normal and suspected abnormal renal tissue should be inclu- MRI studies are inconclusive or contraindicated.
ded in the scan plane.
왘 The MI setting should be adjusted to provide sufficient tissue 3.1.3.3 Vascular diseases
cancellation with maintenance of adequate depth penetra- The diagnostic value of CEUS in detecting or grading renal artery
tion. Major vascular structures and some anatomical land- stenosis (RAS) is still controversial and so far probably not super-
marks should remain barely visible. ior to established Doppler techniques in most patients. However,
왘 UCA is administered as a bolus injection followed by a 5 – it may help to enhance backscatter signals from the renal arter-
10 ml saline flush as described in the liver chapter above. ies and thus decrease the number of inadequate Doppler studies
The needle diameter should not be smaller than 20 Gauge to [95 – 98]. Detection of segmental or subcapsular renal infarction
avoid the loss of bubbles due to mechanical impact during in- and cortial necrosis are strongly improved by CEUS [99].
jection. A stop clock should be started at time of UCA injec-
tion. 3.1.3.4 The transplant kidney
왘 Real time scanning performed for up to 180 seconds is recom- In the transplant kidney, CEUS can help in diagnosing arterial
mended to continuously assess the wash in and wash out and venous thrombosis as well as infarction with great confi-
phases. dence [99, 100]. It can be employed to identify post interven-
왘 In some contrast specific US modes, simultaneous display of tional complications such as bleeding, hematomas, AV shunts
tissue and contrast signals has been implemented. This mod- or large false aneurysms in angiomyolipoma [101].
ality is particularly useful for small lesions to ensure that the
target lesion is kept within the scanning field during CEUS. 3.1.3.5 Renal trauma patient
왘 Because of the dynamic nature of real time CEUS, the investi- See trauma chapter 6.
gation should be documented on video or digital media.
왘 In patients with suspected vascular diseases (mainly small 3.1.4 Recommended uses and indications
vessel diseases) or trauma, long and short axis views should 3.1.4.1 Recommended Indications
be obtained during both the cortical and medullary phases. CEUS is indicated in the following clinical situations:

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
 Guidelines 37

왘 Evaluation of anatomic variations mimicking a renal tumor sensitivity of VUS in reflux detection [14, 16, 17, 19, 102 – 109].
(“pseudo-tumor”). The time needed to perform a VUS may be longer than for a
왘 Characterisation of complex cystic lesions and suspected cys- VCUG but this can be reduced by using advanced contrast ima-
tic renal carcinoma. ging techniques [14, 16, 19]. When VUS is employed in routine
왘 Characterization of thrombus within the renal vein and vena practice there is the potential of more than 50 % reduction of
cava. the number of children undergoing reflux examinations using
왘 Suspected vascular disorders, including renal infarction and ionising radiation [110].
cortical necrosis. The higher cost of UCAs compared to X-ray contrast agents is an
왘 Renal trauma and follow up. impediment to the widespread use of VUS. With the newer UCAs
왘 Patients with contraindications for the use of contrast agents such as SonoVue® there is potential for marked dose reduction
for CT or MR. with the possibility of performing several reflux examinations
using just one vial, where permitted [17 – 20]. This would reduce
3.1.4.2 Limitations the cost of the VUS examinations.
왘 The short enhancement time limits the diagnostic window.
왘 Due to high bubble concentration during the corticomedullar 4.2 Study Procedure
phase, attenuation may cause shadowing in the deepest parts 4.2.1 Preparation
of the kidney. The UCA can be administered via a bladder catheter or supra-
pubic puncture. For the latter, a full bladder is necessary and it
3.2 Detection of Focal Renal Lesions is advisable to apply an anaesthetic plaster at the site of punc-
Despite the fact that today most renal tumours are detected by ture about an hour prior to the examination.
greyscale US, the sensitivity of CEUS is rather low in small tu-
mours when being compared to contrast enhanced CT or MR. 4.2.2 Procedural steps
Except for a small group of patients with an increased risk of The steps recommended in the study procedure are as follows
renal cell carcinoma (i. e. patients with Von Hippel Lindau dis- [14 – 16]:
ease and patients with end stage renal disease), routine use of 왘 Pre-contrast urosonography: baseline documentation of the
CEUS for detection purpose can not be recommended. whole urinary tract in supine ( ± prone) positions, paying par-
ticular attention to the terminal ureters and pelvicalyceal sys-
3.3 Monitoring of local ablative treatment and after tem.
surgery 왘 Intravesical administration of UCA and 0.9 % normal saline
Ultrasound contrast agents may be useful in the immediate as- [111] via transurethral catheter, suprapubic puncture/cathe-
sessment of residual tumor after radiofrequency ablation (see ter. UCA – Levovist® concentration 300 mg/ml; dose 5 – 10%
liver chapter 2.3). They may also be helpful in demonstrating of bladder volume. 0.9 % normal saline – volume is age-de-
postoperative local complications such as bleeding or hemato- pendent.
ma that may mimic a solid renal tumor. 왘 Post-contrast urosonography: monitor UCA administration;
scan terminal ureters and alternatingly – going from side-to-
side – both renal pelves.
4 Vesico-ureteric reflux 왘 Post-contrast voiding urosonography: repeat above scan dur-
! ing and after voiding; the patient can be examined during
4.1 Background voiding in one of the following positions: supine, prone, sit-
In addition to intravascular use, UCAs are suitable for intraca- ting or standing.
vitary administration. Other than hysterosalpingography, the 왘 ± Urethrosonography: transperineal scan of the urethra dur-
main application in this regard is for diagnosis of vesicoureter- ing voiding.
ic reflux (VUR) after intravesical instillation [15]. This is the
most commonly performed contrast-enhanced US examina- 4.2.3 Procedural remarks
tion in children. UCAs markedly boost the US backscatter of 왘 When using Levovist®, fundamental US scanning may suffice
bladder content. Consequently, refluxing microbubbles in the for the diagnosis of reflux. The additional use of colour Dop-
ureter and pelvicalyceal system and flow in the urethra are pler can increase the sensitivity of reflux detection [108, 112,
easily visualized. Levovist® is approved for this indication in 113]. Harmonic imaging has proved to be of considerable ad-
children in a number of countries. vantage in VUS as it markedly increases the conspicuity of the
A few clinical studies using SonoVue® for sonographic reflux microbubbles and the detection rate of reflux [114 – 116].
examination have recently appeared though it is not approved Dedicated high MI imaging incorporating colour overlay of
yet for paediatric use [17]. No clinical side effects of intravesi- the microbubbles, subtraction and dual imaging brings about
cal administration of UCAs have been reported since their in- even more practical improvements.
troduction over a decade ago. 왘 The air in the microbubbles of Levovist® diffuses out very ra-
The intravesical administration of UCAs for diagnosis of vesi- pidly when 0.9 % saline from a vacuum-sealed container is in-
coureteric reflux (VUR), called voiding urosonography (VUS), fused into the bladder. This is because of the low saturation of
has become part of the routine diagnostic imaging modality the solution with air and results in marked shortening of the
options in children [15]. It is used in conjunction with or as a duration of contrast. Physiological saline solutions from plas-
complete replacement for reflux examinations using ionizing tic containers are saturated with air, but those from glass bot-
radiation i. e. voiding cystourethrography (VCUG) and radionu- tles are very rarely so [117].
clide cystography (RNC). Comparative studies, particularly be-
tween VUS and VCUG, have revealed the significantly higher

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
38 Guidelines

왘 SonoVue® is not approved for VUS. Initial clinical studies have Dynamic observation of a given lesion during the arterial, par-
demonstrated that the dose necessary for intravesical admin- enchymal and venous phases should allow a better characteri-
istration is less than 1 % of the bladder volume [17 – 20]. zation and evaluation of its relationship with the peripancrea-
왘 Urethrosonography can be performed as part of VUS. Com- tic arteries and veins.
parative studies have shown its high diagnostic accuracy After completion of the pancreatic study, an evaluation of the li-
compared to VCUG in both boys and girls [118 – 120]. ver in the late phase should be performed exploiting the same
injection [38, 124 – 126, 128 – 131].
4.3 Image interpretation
왘 Reflux diagnosis: reflux is diagnosed when echogenic micro- 5.3 Image Interpretation and Evaluation
bubbles are detected in one or both ureters and/or the pelvi- 5.3.1 Pancreatic carcinoma
calyceal system. Ductal adenocarcinoma is the most frequent pancreatic solid
왘 Reflux grading: the severity is graded into 5 degrees (Grade I– lesion and the most common tumour of the pancreas. At CEUS,
V) similar to the international reflux grading system of VCUG ductal adenocarcinoma is typically hypoenhanced compared to
[121]. the adjacent pancreatic tissue in all phases. This pattern is re-
ported in 88 to 93 % of cases [125, 126, 132 – 140]. The lesion
4.4 Recommended use and indications size and margins are better visualized, as well as the relation-
4.4.1 Recommended indications ship with peripancreatic arteries and veins [125, 126, 135].
The main factor influencing the selection of VUS as the primary Endocrine tumor are characterized by hypervascularization ap-
diagnostic imaging modality has been the necessity of depicting pearing typically hyperenhanced at CEUS [124, 127].
the urethra [110, 122, 123]. The additional scan of the urethra,
even though technically feasible, is not commonly performed. 5.3.2 Pancreatitis
Accordingly, the common selection criteria for VUS are as fol- Focal pancreatitis has been reported to have similar enhance-
lows: ment features to the normal pancreatic parenchyma [133].
왘 Follow-up examination for reflux after conservative or surgi-
cal therapy. 5.3.3 Pseudocysts and cystic tumors
왘 First reflux examination in a girl. CEUS improves the ultrasonographic differential diagnosis be-
왘 Screening for reflux e. g. siblings, transplant kidney. tween pseudocysts and cystic tumors of the pancreas (e. g. mu-
cinous cystadenoma, cystadenocarcinoma) by revealing vascu-
4.4.2 Limitations larization of intralesional inclusions.
VUS is not recommended, particularly as the primary imaging Pseudocysts, the most common cystic lesions of the pancreas,
modality for reflux, in the following conditions: are non-vascularised: they do not show any signal at CEUS and
왘 The bladder or one of the kidneys is not depicted on US e. g. in remain completely anechoic in all phases, even when they are
severe scoliosis. inhomogeneous on US. In some cases, peripancreatic vessels
왘 Routine evaluation of urethra (first reflux examination in may be seen trapped inside the pseudocyst. Cystic pancreatic
boys). tumors usually have vascularized septa and parietal nodules
왘 Assessment of bladder function. [141].
The reported sensitivity and specificity of CEUS in characteris-
ing pseudocysts is up to 100% [138].
5 Pancreas
! 5.4 Recommended uses and indications
5.1 Background All the pancreatic lesions, in the absence of clear cut signs of
The study of the pancreas is a new and promising application of malignancy (e. g. liver metastases), found at US should be stu-
contrast-enhanced ultrasonography (CEUS), including contrast- died with CEUS in order to improve:
enhanced endoscopic ultrasound, and some recommendations 왘 depiction of the dimensions and margins of the lesion includ-
may be now proposed. ing its relationship with adjacent vessels,
Contrast-enhanced ultrasonography (CEUS) is not indicated to 왘 characterization of the lesion (e. g. ductal adenocarcinoma,
date to improve the detection of pancreatic lesions. CEUS can be endocrine tumor),
used to improve delineation of pancreatic lesions compared to 왘 differential diagnosis between pseudocyst and cystic tumors,
conventional ultrasound (US) or to characterize lesions already 왘 differentiation of the vascular (solid) or avascular (liquid/ne-
visible at US [124 – 127]. The use of CEUS in this indication has crotic) components of the lesion.
not yet obtained regulatory appoval and thus represents an off-
label use, which should be justified by an individual risk/benefit
assessment for the respective patient, based on the available sci- 6 Blunt abdominal trauma
entific data. !
6.1 Background
5.2 Study procedure Contrast enhanced CT (CECT) is the obvious modality of choice
The blood supply of the pancreas is entirely arterial. Enhance- for the detection of parenchymal, skeletal and neurological da-
ment of the pancreatic gland begins almost at the same time mage, haemorrhage and thoracic injuries in all cases of high-en-
as aortic enhancement. After this early phase (arterial/pancrea- ergy multitrauma. However, there is a wide range of severity
tic; from 10 to 30 sec) the venous/late phase persists for a short among trauma patients who are admitted to an emergency
time (from 30 to approximately 120 sec) [124 – 126]. unit, and positive findings on CECT decrease with lower trauma
energy. Many patients who have suffered low energy trauma are

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
 Guidelines 39

haemodynamically stable and are able to cooperate. A large 6.3 Recommended uses and indications
sub-group of low energy trauma patients have suffered blunt Since CEUS is not capable of screening the entire abdomen as
trauma to one abdominal flank. In this group the liver, spleen it is possible with CECT, care must be taken not to perform
and kidneys are the parenchymal organs that are by far the CEUS instead of CECT as the first hand modality in cases where
most prone to injury, and a substantial proportion of these pa- there is a clinically appreciable risk of injury to organs other
tients have no injuries on CECT. This should be weighed against than the spleen, liver or kidneys. Isolated low energy trauma
the negative implications of CECT, which are the exposure to to one flank very rarely involves other organs, but the trauma
ionizing radiation and the injection of iodinated contrast. These pattern must be assessed by the clinician in charge of each
negative implications become even more important as many of clinical case. The use of CEUS in this indication has not yet ob-
these patients are young and otherwise healthy. tained regulatory appoval and thus represents an off-label use,
Conventional greyscale ultrasound (US) is used around the which should be justified by an individual risk/benefit assess-
world for assessment of free fluid in the abdomen in cases of ment for the respective patient, based on the available scienti-
trauma (FAST, or Focused Assessment with Sonography fic data.
in Trauma). However, US has major limitations for the detec- CEUS can sometimes be successfully used as an adjunct to mul-
tion of parenchymal lacerations and even large lacerations can titrauma CECT in trauma cases where the CECT exam is of poor
be undetectable. quality due to artefacts. Focused CEUS of an organ with equivo-
cal results on CECT may establish or rule out injury in the par-
6.2 Study procedures ticular area of interest.
Befor the CEUS exam begins, a US according to a FAST proto- CEUS should be considered for initial detection of lacerations,
col is performed in order to detect or exclude the presence of fresh subcapsular haematomas and fluid collections around the
free fluid. The liver, spleen and kidneys are examined with US. organs. It can also be useful to follow up known parenchymal
If it is determined that these can not be fully visualized, CEUS injuries in order to avoid unnecessary repeat CECT with its risks.
is not performed and CT is recommended. Thus, an initial CEUS examination may be useful at the time of
Contrary to malignant or benign solid lesions, there is no circula- the CECT when follow-ups can be expected.
tion at all in haematomas or lacerations unless there is ongoing
bleeding. This means that the detection of injuries is possible in 6.3.1 Recommended indications
all circulatory phases of the organs. Repeated small doses of UCA 왘 CEUS is recommended in addition to FAST and US in the eva-
give the examiner more time for a thorough examination. luation of traumatic parenchymal injuries to the liver, spleen
and kidneys.
6.2.1 The liver
Active bleeding is best seen during the arterial phase, and lacera-
tions are best seen when there is homogenous enhancement in 7 Transcranial Ultrasound
the liver in the late phase. Two to three minutes after the first in- !
jection, a second administration of half the amount of the first 7.1 Background
bolus may be given to provide more time for scanning. The general indication for the use of transpulmonary UCAs in in-
vestigations of the cerebral arteries is a poor signal-to-noise ra-
6.2.2 The spleen tio with unenhanced Doppler. Moreover, difficult diagnostic pro-
The spleen generally enhances intensely for a long time, which blems are often encountered in unenhanced transcranial color-
may cause self-shadowing of the deepest parts by the UCA. In- coded sonography (TCCS) such as apparent “no flow, slow flow
itially about one-fourth of a normal liver dose of UCA is re- or low flow” phenomena. In such cases, administration of UCA
commended. The parenchyma of the spleen initially enhances enables differentiation between vessel occlusion and poor inso-
in a patchy pattern, and the parenchyma is generally not even- nation conditions as well as detection of very slow blood flow
ly enhanced until about 40 seconds following the bolus. Once velocities and low blood volume (● " Table 4).

the parenchyma is evenly enhanced there is usually ample Contrast-enhanced transcranial color-coded duplex sonography
time for a thorough examination of the spleen without a rein- (CE-TCCS) is the best ultrasound technique for contrast ima-
jection. After a few minutes the veins of the spleen have been ging, as it provides simultaneous B-mode depiction of brain
washed out and may mimic lacerations, but the veins can ea- anatomy, which can be optimized without the Doppler signal.
sily be defined as veins from to residual UCA signals and their After UCA administration, the contrast agent can be detected
typical anatomy. simultaneously in several vessels.
UCAs can also be used to image brain perfusion in patients with
6.2.3 The kidneys cerebrovascular disease. This is because UCA can be detected in
Normally there is intense enhancement of the renal parenchy- the cerebral microcirculation through a unique interaction with
ma, and initially one-fourth to one half of a normal liver dose the ultrasound energy, thus allowing UCAs to serve as surrogate
of UCA is recommended. There is a fast turnaround of the UCA markers for blood. Of the approaches that have been developed
in the kidneys so that the enhancement usually results in only for brain perfusion imaging, most clinical experience has been
about two minutes of effective scanning. Scanning for injuries obtained with bolus kinetics. Other methods, which can be clas-
may begin immediately since most lacerations include the cor- sified as experimental, include refill kinetics and diminution ki-
tex. Since the kidneys are limited in size and can usually be cov- netics. Real-time, low mechanical index imaging with UCA is a
ered in two planes fairly quickly, two minutes is usually enough particularly promising new application for evaluation of brain
for thorough scanning. If not, a reinjection of about half the ori- perfusion.
ginal bolus prolongs the available examination time.

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
40 Guidelines

diagnostic clinical example Table 4 Indications for the appli-

problem cation of UCAs in neurovascular
imaging of extra- or intracranial
intracranial extracranial brain supplying arteries
poor ultrasound – poor temporal acoustic window – ultrasound attenuation by calcified carotid artery
penetration – insonation of arteries at the stenosis or postoperative edema (carotid-TEA)
contralateral hemisphere – anatomy: deeper arteries at the skull base (ACI-
dissection)
slow blood flow – subtotal stenosis – subtotal stenosis (intra- or poststenotic)
velocity – aneurysm/AVM
– vein/cerebral sinus
low signal – detection of small vessels – residual lumen of a subtotal stenosis with high blood
intensity – detection of cerebral micro- flow velocity
circulation (tissue perfusion)

7.2 Study Procedures 7.3.2 Perfusion imaging

There are two general procedures using UCA bolus application. After UCA bolus injection, time intensity curves (TICs) with
wash-in and washout phases can be generated using contrast-
7.2.1 Vascular imaging specific imaging and further analyzed. Different parameters of
왘 Transtemporal or transnuchal insonation in the axial planes these curves can be extracted, such as time to peak intensity,
with an insonation depth of 10 to 12 cm (transtemporal arter- peak width, or area under the transit curve.
ial investigation site ipsilateral to the probe). Coronal trans-
temporal insonation planes may also be used. 7.4 Recommended Uses and Indications
왘 After optimizing the acoustic bone window, the UCA is admi- 7.4.1 Examination of the anterior circulation
nistered as a bolus injection: Insonation through the temporal bone window can be impaired
왘 Levovist®: the UCA is injected intravenously as a bolus (5 – by a poor signal-to-noise ratio, especially in elderly patients in
10 ml at the concentration of 400 mg/ml), followed by whom the bone is thickened. This can be overcome in most pa-
10 ml saline flush, tients with CE-TCCS. After administration of UCA, over 85 % of
왘 SonoVue®: the UCA is injected intravenously as a bolus of examinations of the middle cerebral artery, the anterior cere-
1 – 2 ml (up to 4.8 ml) followed by 10 ml saline flush. bral artery, the P 1 and P 2 segments of the posterior cerebral ar-
tery, and the supraclinoid portion of the internal carotid artery
7.2.2 Perfusion imaging siphon are satisfactory.
왘 Transtemporal insonation in the axial plane with an insona-
tion depth of 10 to 12 cm (ischemic lesion ipsilateral to the 7.4.2 Examination of the posterior circulation
probe). Other insonation planes may also be used. Examinations of the intracranial vertebral arteries and the ba-
왘 After optimizing the acoustic bone window with convention- silar artery are also facilitated by UCA. CE-TCCS through the
al B-Mode imaging, UCA is administered as a bolus injection: foramen magnum can increase the depth at which vessels can
왘 Levovist®: the UCA is injected intravenously as a bolus be identified and improve the number of pathologic findings
(10 ml [1 – 2 ml/s], 400 mg/ml), followed by 10 ml saline not seen in unenhanced scans and improve diagnostic confi-
flush. dence. UCA can also improve the detection of cerebellar artery
왘 SonoVue®: the UCA is injected intravenously as a bolus segments.
(2 ml [up to 4.8m]) followed by 10 ml saline flush.
7.4.3 UCAs in patients with internal carotid artery (ICA)
7.3 Image Interpretation and Evaluation stenosis
7.3.1 Vascular Imaging Particularly in patients with ICA stenosis and insufficient bone
In most cases, CE-TCCS is used to differentiate between vessel windows, characterization of collateral flow in the circle of
occlusion and poor insonation conditions as well as for the Willis with UCA is important for estimating the hemodynamic
detection of very slow blood flow velocities and low flow vo- risk of borderzone infarction in the ipsilateral cerebral hemi-
lumes (small vessels, vessel pseudo-occlusion). Beside the col- sphere. When undergoing carotid endarterectomy, patients
or information of the CE-TCCS the simultaneous Doppler fre- with absence of collateral flow are particularly vulnerable dur-
quency spectrum recording adds important haemodynamic ing carotid artery cross clamping. Thus, the use of UCA in pa-
information for the interpretation of the investigation. tients with carotid stenosis and poor temporal bone windows
Several technical artifacts should be considered when using CE- can provide valuable information for patient management.
TCCS. Bolus application leads to peak concentrations of UCA that
overload the ultrasound system with an overshoot of color sig- 7.4.4 UCAs in stroke patients
nals (``blooming''). Doppler spectra cannot be measured in this Recent studies in stroke patients have documented successful
early phase. The blooming artifact can be reduced by choosing a examination of the basal cerebral arteries in only 55 % with un-
lower signal amplification or by using an UCA infusion. It decrea- enhanced TCCS. Fortunately, reliable diagnosis can be obtained
ses with falling UCA concentration. UCA injection leads to an ar- in 90% of acute stroke patients after contrast enhancement. Cor-
tificial increase (15 – 36 %) in maximum blood flow velocity [142, respondingly, in patients eligible for recombinant tissue-type
143]. This technical artifact should be considered when using ve- plasminogen activator (rt-PA) thrombolysis, it may be advanta-
locity criteria in the classification of stenoses. geous to administer UCA without prior unenhanced scanning.

EFSUMB Study Group et al. Guidelines and Good… Ultraschall in Med 2008; 29: 28 – 44
 Guidelines 41

15
In patients with successful CE-TCCS exams receiving correlative Academisch Ziekenhuis, Rotterdam, Netherlands
16
Clinical Sciences Centre, Imperial College London, UK
angiography (MR, CTA or conventional angiography) the find- 17
Division of Diagnostic and Interventional Radiology, Department of Oncol-
ings are identical in over 95 %. ogy, Transplants and Advanced Tecnologies in Medicine University of Pisa,
Italy
18
Department of Radiology, John Radcliffe Hospital Oxford, UK
7.5 Limitations 19
Servizio di Radiologia, Como. Italy
왘 Despite administration of UCA, only the proximal segments 20
Neurologische Klinik, Universitätsklinikum Mannheim, Germany
21
of the basilar artery can be investigated. The distal portion Department of Radiology, Køge Hospital, University of Copenhagen,
Denmark
can be examined using the transtemporal approach which 22
Spec. Medicina Interna. Dottore Di Recerca In Ultrasonologia in Medicina,
leaves the middle portion of the basilar artery as a diagnostic Dirigente Medico I Livello, Bologna, Italy
23
gap in CE-TCCS. Dipartimento Di Science Radiologiche Azienda Policlinico Umberto I,
Roma, Italy
왘 The quality of transtemporal precontrast scans is strongly 24
Department of Neurology University of Schleswig-Holstein, Lübeck,
predictive of the potential diagnostic benefit from adminis- Germany
25
tration of an UCA. In patients whose intracranial structures Herlev Hospital, Copenhagen University, Denmark
26
Department of Radiology, General Hospital of Busto Arsizio, Italy
are not visible on B-mode imaging and whose vessel seg- 27
Radiologisk Afdeling Herlev Hospital, Denmark
ments are not depicted with color Doppler, there is little 28
Unité Fonctionnelle Ultrasons Directeur CIT, Tour, France
29
chance that a contrast agent will provide diagnostic informa- Krankenhaus Siloah, Med. Klinik II, Hannover, Germany
30
Regional Medical Physics Dept, Newcastle General Hospital, UK
tion. On the other hand, precontrast identification of any cer-
ebral artery strongly predicts a conclusive investigation with
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