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Ultrasound contrast agents
First-generation ultrasound contrast agents contained microbubbles of air that were dissolved in blood when exposed to acoustic pressure in the ultrasound field. First-generation contrast agents were therefore present in the bloodstream for a limited time 1. Examples include:
Levovist (Bayer AG) 13
Second-generation contrast agents include microbubbles of perfluorocarbon, nitrogen gas or sulfur hexafluoride stabilized in a phospholipid membrane. The bubbles oscillate when exposed to the ultrasound beam (they are being compressed by the effect of positive pressure created by the ultrasound waves and they expand in the negative pressure phase). The compression of the gas is greater than expansion which creates a non-linear response (echo). This greatly affects ultrasound backscatter and increases vascular contrast in a similar manner to intravenous contrast media used in CT and MRI 2.
Examples of ultrasound contrast agents (brand names) available commercially 12,13:
Definity (Lantheus Medical Imaging)
Optison (GE Healthcare)
Sonazoid (GE Healthcare)
SonoVue is a purely intravascular contrast agent, therefore it allows assessment of the vascularity and non-specific contrast agent retention of lesions. Due to its widespread approval, it is by far the most commonly utilized ultrasound contrast agent currently.
In comparison Sonazoid is taken up by Kupffer cells of the liver due to its hydrogenated egg phosphatidylserine sodium coating, leading to persistent contrast enhancement of the liver in the postvascular phase. As metastases to the liver do not contain Kupffer cells, Sonazoid-enhanced US could improve detection and characterization by demonstrating late-phase hypoenhancement. It can also aid detection of liver tumors such as hepatocellular cancer which are typically demonstrating early vascular phase hyperenhancement, whilst the absence of postvascular phase iso/hyperenhancement is a strong indicator of malignant transformation. Thus, Sonazoid could improve differentiation of e.g. regenerative and dysplastic nodules in a cirrhotic liver from early phase hepatocellular carcinomas. As of 2020, Sonazoid is only approved for clinical use in a select few countries 11.
Contrast-enhanced ultrasound has the advantage over contrast-enhanced MRI and CT in patients with contraindications such as renal failure or iodinated contrast allergy. Contrast-enhanced ultrasound also allows for dynamic and repeat examinations.
An individual microbubble is estimated to measure ~6 micrometers, compared to a human erythrocyte measuring ~9 micrometers. Microbubbles are therefore not filtered in the lungs since they are equivalent in size to red blood cells. Microbubbles are different from the agitated saline used in echocardiographic "bubble studies".
The microbubbles used for contrast-enhanced ultrasound are sensitive to insonation, and as a consequence can easily be depleted by overscanning during the arterial and portal phase, potentially jeopardizing the detection of e.g. late phase wash-out. This feature can be however also exploited by deliberately destructing them using a single ultrasound pulse with very high mechanical index, commonly termed "flash" 8. Such an option is nowadays available in most contrast-enhanced ultrasound-capable scanners and allows for the evaluation of slower, e.g. venous phase, contrast refill/reperfusion of a lesion or tissue (termed flash-replenishment technique 9), it can also be used to clear residual contrast signal from the area of interest before a contrast reinjection.
Non-targeted contrast-enhanced ultrasound
The more common method
dynamic evaluation of the vascularity of a target lesion, most commonly in the liver or kidney, may be useful in diagnosis
used to measure organ perfusion, which can be useful in diagnosing diffuse processes (e.g. cirrhosis)
Vascular CEUS contrast agents demonstrate distinct enhancement phases much like CT and MRI contrast media:
arterial phase (up to 25 s postinjection)
portal venous phase (25-45 s postinjection)
late phase (at least 2 minutes postinjection) 10
Sonazoid as discussed earlier is taken up by the Kupffer-cells, and therefore it has a late postvascular phase where lesions without such cells (e.g. metastases to the liver) can be better discerned.
Targeted contrast-enhanced ultrasound
Contrast agents are designed to bind to specific molecules, which are then targeted at tissues expressing that substance.
Contrast-enhanced voiding urosonography is a special type of CEUS exam for which the diluted microbubbles are given intravesically via a urinary catheter. It is mainly used for the evaluation of vesicoureteral reflux in pediatric patients.
Contrast-enhanced ultrasound artifacts
In very rare cases contrast-enhanced ultrasound contrast agents may accumulate in the liver and cause inhomogeneous, often confluent hyperechoic regions, or acoustic shadowing without associated clinical symptoms. This is termed prolonged heterogeneous liver enhancement and is a benign, self-limiting artifact. If high mechanical index scanning (e.g. standard B-mode) is used after the injection of the contrast agent a migrating echogenic band can be visualized (northern lights phenomenon), which represents the wavefront of microbubble burst.
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