Contrast-enhanced ultrasonography : does it have a role in developing countries ?

Contrast-enhanced ultrasonography (CEUS) has become an extremely useful adjunct to conventional ultrasound, and in many clinical situations it may replace or obviate the need for CT or MRI. Its use in developed countries has been variable, but it is suggested that in developing countries where CT and MRI have more limited availability, CEUS has great potential. This article explains why the author believes this to be the case, introduces the technique and describes the clinical roles to which CEUS may be applied.


Introduction
Contrast-enhanced Ultrasonography (CEUS) has been in clinical use for many years, its most widespread application having been in cardiology.Advances in the contrast agents have lead to the ability of modern generation of the microbubbles to transit from peripheral veins, through the lung vasculature to the systemic circulation, and to recirculate for several minutes.This has resulted in the clinical roles to widen markedly.Only the non-cardiological roles will be discussed in this article.
CEUS has become an extremely useful adjunct to conventional ultrasound 1,2 and, in many scenarios, may replace contrastenhanced CT or MRI, particularly in the examination of the solid viscera of the abdomen.
Despite this, its uptake in developed countries has been variable.CEUS is widely used in parts of Europe.However, in Australia, for example, CEUS is essentially confined to major public health centres 3 , partly due to the fee structure for medical procedures, partly due to the lack of incentive (and possibly the presence of a disincentive in private radiology practice) to the use of CEUS when CT and MRI are liberally available, and perhaps also partly due to the diminishing 'hands-on' experience of radiologists in US examinations.In the USA, while similar factors may apply, a major issue is that the recent generation of contrast agents has not been approved by the Food and Drugs Administration.The causes for this patchy uptake in the developed world was excellently summarized by Sidhu 4 in 2008.Since then the impression is that progress has been slow.However, there is a huge untapped potential for CEUS in the developing world and this article discusses the advantages of CEUS in the context of the health system of those countries where access to CT and, in particular, MRI is limited.It is my understanding that in Sri Lanka, for example, outside the major population centres, CT and MRI are present in the minority of sites, whereas US is second only to plain radiography in availability.
When CEUS is a viable clinical alternative to CT and MRI, its advantages include: 4).CEUS can be performed immediatelyat the same attendance as the conventional US 5).CEUS can be undertaken at the bedside, in the Emergency Room or clinic 6).The contrast agents are safe, even in the presence of renal impairment, with no need for preliminary laboratory testing.7).The contrast is relatively cheap.8).Lack of ionizing radiation (cf CT) 9).The contrast medium is administered by peripheral intravenous injection.

Ultrasound Contrast and Technique
Latest generation US contrast agents consist SLJR Vol.1 2015 of microbubbles of stable perfluorocarbon or sulfur hexafluoride gas in a tough shell of albumen or phospholipids.They are administered by peripheral intravenous injection and are predominantly blood pool agents -that is they remain within the intravascular space, unlike the majority of CT and MRI contrast agents.
The encapsulated microbubbles measure <10 µm and thus pass through the pulmonary and systemic circulation and are durable enough to re-circulate for several minutes .The limited diffusion of the inert gas, as well as its low solubility, contribute to the persistence of the microspheres in the blood.The gas is inert, is not metabolised and is eliminated through the lungs within 10 minutes of administration.US contrast agents work by increasing the strength of the backscattered signals from blood by several orders of magnitude.Imaging is acquired in real time as the agent enhances the vascular structures within normal and pathological structures.Effectively a 'real-time' US angiogram is obtained over several minutes, if required, during multiple vascular phases.
Contrast-specific scanning modes are required on the US machine 5 .These modes use a low mechanical index (MI) to avoid bursting the bubbles on insonation and are usually a variant of contrast harmonic imaging /phase inversion techniques.'Flash' imaging can be used as an adjunct; this entails transiently increasing the MI to deliberately disrupt the microbubbles within the insonated area, and then returning to low MI to visualize contrast replenishment within the area of interest.
Images can be interpreted qualitatively (Figs 1 -3) and quantitatively (Fig 4).Quantitative assessment is achieved by prescribing regions of interest (ROI) in the image 6 .The software then plots Time versus Intensity curves (TICs) that it displays graphically.TICs are very useful to measure various objective parameters, such as time-to-peak intensity, maximum intensity, area-underthe-curve, wash-out, etc.This helps to characterise lesions, particularly when ROIs from a lesion (and even from different parts of a lesion) and surrounding normal tissue are compared.There is a theoretical risk that US with contrast agents could result in bioeffects.Experimental data from their use in small animals indicate that rupture of microvessels could occur when gas bodies are insonated.If this is a real risk it is likely only to be clinically significant when CEUS is used for ocular roles and when insonating brain without an intact skull 7 .With regard to contraindications, it was previously considered that patients with right-to-left cardiac shunts should not be given US contrast agents.However, recent data suggest that this should no longer be considered to be the case in adults 8,9 .

US contrast agents
Caution should be taken when considering CEUS in patients with pulmonary hypertension and "unstable cardiopulmonary conditions", although in cardiology patients requiring echocardiography, the benefits of using US contrast agents may over-ride the risks 10 .
For the contrast agents in which the shell of the microbubble is albumin, a history of allergy to albumin or blood products should be sought as a contraindication.

Technical limitations
EUS is subject to the limitations of conventional US, including unfavourable body habitus and interposition of gas or bone between the skin surface and the target lesion.In addition, due to the nature of the CEUS scanning modes, deep lesions may not be able to be adequately examined with CEUS.

Clinical roles
CEUS provides a good alternative to CT and MRI in the examination of many solid organs, especially in the abdomen, and of vascular structures.The enhancement patterns of lesions can be studied during multiple vascular phases -arterial, portal venous, late and post-vascular phases -in a similar fashion to contrast-enhanced CT and contrast-enhanced MRI, but in real time with a resultant much higher temporal resolution than is possible with CT or MRI.
The real-time nature of CEUS allows depiction of early arterial phase enhancement, which is sometimes missed on CT and MRI because of their lower 'frame rates'.The following is a noncomprehensive list of the applications of CEUS in various organs and clinical scenarios.
Liver 2 1).CEUS has proven useful in the characterization of focal liver lesions (FLLs).It is particularly useful for differentiating benign and malignant nodules 11,12 .CEUS shows tissue perfusion analogous to that shown on contrastenhanced CT and MRI in which patterns of enhancement in the arterial and portal venous phases predict the diagnoses of FLLs 2,13-16 and has been shown to be comparable to CT and MRI 17 and useful as a first line investigation of FLLs 15 .Most malignant lesions show 'wash-out' of contrast agent on portal venous or later phases (Fig 5).2).For metastasis detection in patients with non-hepatic primary tumours, CEUS is better than conventional ultrasound 18 , but probably less sensitive than multi-detector CT on a lesion-by-lesion analysis 19,20 3).The use of CEUS is cost-efficient in the first-line diagnosis of FLLs compared to CT and MRI 21 .CEUS can often establish a definitive diagnosis or otherwise aid in deciding whether a liver lesion needs further investigation.4).Simple algorithms allow diagnosis of most liver masses 22 .5).CEUS has been found to improve the characterisation of focal liver lesions with enhancement patterns observed during the arterial, portal venous and late phases generally similar to CECT and CEMRI.6).CEUS is valuable for the evaluation of nodules in the patient at risk for hepatocellular carcinoma 23,24 . 7).CEUS can differentiate between adenoma and focal nodular hyperplasia in asymptomatic young women 25,26 (Fig 6).
Renal applications CEUS provides information on tissue perfusion and may play a role in kidney mass characterization similar to the role of contrast-enhanced CT and MRI 1,27 .Specific roles in the kidney include: 1).Differentiation of solid and cystic lesions in hypovascular masses.2).CEUS significantly improves diagnostic confidence for solid renal masses.
The overall accuracy for renal carcinoma has been shown to be 90% 28 .
3).CEUS is useful for the diagnosis of renal pseudo-tumours , reducing the need for CT 29 .4).CEUS enables Bosniak classification of complex renal cysts without the need for CT 30 .5).Investigation of suspected renal infarction -total or segmental 6).Vesico-ureteric reflux in girls after introduction of US contrast material into the bladder.

Scrotal imaging
CEUS is useful in patients with acute scrotal pain 31 and trauma 32. 1).In the differentiation of hypovascular and avascular lesions, the latter being indicative of benign disease 2).Discrimination of areas of non-viable tissue in cases of testicular trauma 3).Discrimination of abscess formation in severe epididymo-orchitis.4).Detection of segmental infarction.

Pancreas
CEUS has been shown to be effective in: 1).The characterisation, delineation and local staging of adenocarcinoma 33 .2).The discrimination of mass-forming chronic pancreatitis and adenocarcinoma 34 .
3).The differentiation of cystic tumours from pseudocysts 35 .4).Assessing hypervascular masses such as neuroendocrine tumours of the pancreas 36,37 .Fig. 5. TIC of hepatocellular cancer.The TIC shows arterial enhancement of the lesion, similar to surrounding liver, followed by 'wash-out' of contrast from the lesion i.e. lesion becomes iso-echoic to liver SLJR Vol.1 2015 Trauma CEUS has been shown to be an accurate technique for evaluating traumatic lesions of solid abdominal organs 38,39 .However, it has been suggested that its use should be as a first-line approach in patients with lowenergy isolated abdominal trauma, as it shows a high sensitivity both in lesion detection and grading, but that CT should be performed in CEUS-positive patients to exclude active bleeding and urinomas 40 .It is also useful for monitoring patients undergoing conservative treatment in mild degrees of liver and spleen trauma 41 .

Non-cardiological vascular roles
CEUS may be used in a variety of vascular applications, including: 1).Improving US visualization of technically difficult vessels, such as the renal arteries in suspected renal artery stenosis 42 .
2).Differentiation between severe stenosis and complete occlusion of major vessels, including visceral and cerebral arteries.In the carotid arteries CEUS improves the sensitivity of Doppler US and can be used for differentiating complete occlusion from residual flow in tight stenosis.CEUS can be also be utilised to improve the delineation of the inner vascular wall, enabling detection of the configuration of pre-stenotic, intrastenotic and post-stenotic segments and evaluation of neovascularization of plaque (which may be a precursor of plaque rupture) 43 .

Other applications
There are many other potential roles for CEUS, many of which await sufficient evidence of efficacy for clinical application.Examples include the investigation of gynaecological masses, assessment of renal transplants and intracavitary uses, such as voiding urosonography and imaging of Fallopian tube patency.

Conclusion
Contrast-enhanced ultrasonography is a procedure that holds great potential in the context of the health system of a developing country, where access to CT and MRI is limited.It is safe, relatively inexpensive, to a large extent can be applied with only relatively minor modification to existing resources, has a wide range of common clinical applications and may obviate the need in many patients for transfer to a major centre for CT or MRI.

Fig. 1 A
Fig.1 A,B,C.Serial images after IV US contrast agent of a liver haemangioma showing typical 'filling-in' of lesion from rim extending centrally.

Fig. 2 AFig. 3 .
Fig.2 A,B.Serial images -early (A) and delayed (b) -after IV US contrast agent of hepatic Focal Nodular Hyperplasia, (FNH) showing early hyper-enhancement of the lesion with persistence of enhancement in (B).Note central 'scar' in (B)

Fig. 4 A
Fig.4 A, B. Same patients as Fig.1and Fig.2, respectively.Time Intensity Curves (TICs) confirming graphically the enhancement of the lesion (yellow line) relative to normal liver (green line).

Fig. 6 A
Fig.6 A,B.FNH (a) and adenoma (b).TICs from rim of lesion, central lesion and normal liver, showing different patterns of enhancement.FNH shows early enhancement of central portion followed by rim.Adenoma tends to show opposite pattern Vol.1 2015 Kim, T.K., et al., Focal nodular hyperplasia and hepatic adenoma: differentiation with low-mechanicalindex contrast-enhanced sonography.