CONTRAST-ENHANCED ULTRASOUND IMAGING

Contrast-enhanced ultrasound (CEUS) involves the administration of intravenous contrast agents containing microbubbles of perfluorocarbon or nitrogen gas.

The microbububbles affect ultrasound backscatter and increase vascular contrast in a similar manner to intravenous contrast agents used in CT and MRI 

PRINCIPLE

Microbubble shell material determines how easily the microbubble is taken up by the immune system.

The material for microbubble determines its time in circulation and elasticity.

 Microbubble shells are composed of albumin, galactose, lipid, or polymers

Microbubble gas core is the most important part because it determines the echogenicity.

MICROBUBBLE

Size of Microbubble is around  1 - 4 μm. The Microbubble is nearly around the size of

RBCs as it should not cross the vascular endothelium.

Air (Nitrogen) Perfluorocarbon Sulfur hexafluoride

Albunex (Mallinckrodt)

BR14 (Bracco) SonoVue (Bracco)e

Echovist (Shering) Definity (Bristol–Myers Squibb Medical Imaging)

Levovist (Shering) Echogen (Sonus Pharmaceuticals)

Myomap (Quadrant) Imagent–Imavist (Alliance)

Quantison (Quadrant) Optison (GE Healthcare)

MARKET AVAILABLE MICROBUBBLES

Echovist- Used in Right heart Myocardium, Liver and gynaecological applications.

Albunex- used in Liver, Kidneys and heart contrast imaging.

SonoVue- Most Commonly used in INDIA. Used in study of Liver, Kidneys and

Gynaecological studies.

COMMONLY USED MICROBUBBLES

DOSE- . SonoVue is a kit including 1 vial containing 25 mg of lyophilised powder and second vial contains suspension medium (Galactose solution)

For I.V. use dose for SonoVue is 2.4 ml (0.04ml/kg).

For renal and pancreatic evaluation low dose 1.0ml is used.

10ml 0.9% N.S should be flushed after the administration of the contrast agent.

TECHNIQUE OF CEUS

PROCEDURE- The suspension should be administered

before 15mins after preparation. The target organ is focused on B-mode US

and then contrast-specific imaging mode is turned on.

On Ultrasound after the contrast is administered the tissue is divided on basis of Perfussion i.e Hyperenhancing, isoenhancing, hypoenhancing.

1.Non-targeted contrast-enhanced ultrasound

2.Targeted contrast-enhanced ultrasound

TYPES

More common method  In this the microbubbles will remain in the

systemic circulation for a certain period of time. During that time, ultrasound waves are directed on the area of interest. When microbubbles in the blood flow past the imaging window, the microbubbles’ compressible reflect a unique echo. 

Non-targeted contrast-enhanced ultrasound

To enhance the contrast at the interface between the tissue and blood. A clearer picture of the structure of an organ

Evaluating the degree of blood perfusion and evaluating the blood volume in an organ or area of interest. 

Differentiation between benign and malignant focal liver lesions

USES OF NON-TARGETED CEUS

Typical appearance of liver hemangioma (arrows). CEUS shows globular peripheral enhancement 40seconds after microbubble injection (A) and progressive, centripetal fill-in after 90 seconds (B). The centralportion of the lesions remains unenhanced because of incomplete filling in.

Appearance of prostate cancer at CEUS. (A) Baseline transrectal US of the prostate shows no focal abnormalities in the peripheral portion of the gland. (B) Twenty-eight seconds after microbubble injection a hypervascular area is recognized in the right prostate lobe (arrowheads). Cancer was found at biopsy

Acute splenic infarction from septic embolism in a patient with aortic valve prosthesis infection and bacterial endocarditis. (A) No defined abnormalities of the splenic parenchyma are seen on baseline US. (B)CEUS image obtained 30 seconds after microbubble injection shows a large, nonperfused area (*) involving the dome of the spleen

LIVER ABCESS

Contrast agents designed to bind to specific molecules, which are then targeted at tissues expressing that substance.

Microbubbles targeted with ligands that bind certain molecular markers that are expressed by the area of imaging.

Microbubbles theoretically travel through the circulatory system, eventually finding their respective targets and binding specifically. 

Targeted contrast-enhanced ultrasound

Inflammation: Contrast agents may be designed to bind to certain proteins that become expressed in inflammatory diseases such as Crohn's disease, atherosclerosis, and even heart attacks

Thrombosis and thrombolysis: Contrast Agents specifically bind to activated platelets and allow real-time molecular imaging of thrombosis, such as in myocardial infarction, as well as monitoring success or failure of pharmacological thrombolysis.

USES OF TARGETED CEUS

Cancers:  If microbubbles are targeted with ligands that bind receptors like VEGF, they can non-invasively and specifically identify areas of cancers.

Drug Delivery: drugs can be incorporated into the microbubble’s lipid shell.

Gene Delivery: Vector DNA can be conjugated to the microbubbles

FOCAL LIVER LESIONS

Complex hepatic cyst (curved arrows). (A) Baseline US showing a heterogeneous round lesion with well-defined margins but no defined posterior enhancement. (B) After microbubble injection the lesion does not enhance in all vascular phases.

Prostate Cancer

DRUG DELIVERY.

ADVERSE EVENT FREQUENCY 0.5-5 %

FREQUENCY<1%

SYSTEMIC HEADACHEHYPERSENSITIVITY

ABDOMINAL PAIN WEAKNESSCHEST PAIN, BACK PAIN.

CARDIOVASCULAR HYPERTENSION ATRIAL FIBRILATIONPALPITATION, TACHYCARDIA

DIGESTIVE SYSTEM NAUSEA ANOREXIA , DIARRHEA, DYSPEPSIA

MSK, CNS DIZINESS, DRYMOUTH,VASODILATATION

LEG CRAMPS, PARESTHESIA

RESPIRATORY, SKIN DYSPNOEA, SWEATING, RASH, PRURITUS

SPECIAL SENSES ALTERED TASTE, SMELL.

ADVERSE REACTIONS

To reduce the risk Check for intolerance of any of the components of the contrast agent

Use the lowest level of acoustic output and shortest scanning time to allow a diagnostic examination

Management of Drug reactions is symptomatic.

HOW TO REDUCE RISK AND MANAGEMENT.

Acoustically homogeneous. Blood and surrounding tissues have similar echogenicities, so it is also difficult to clearly discern the degree of blood flow, perfusion, or the interface between the tissue and blood using traditional ultrasound.

Allows real-time evaluation of blood flow. Destruction of microbubbles by ultrasound in

the image plane allows absolute quantification of tissue perfusion.

It does not involve radiation.

Advantages of CEUS

Very cost-efficient and widely available. Since microbubbles can generate such

strong signals, a lower intravenous dosage is needed, micrograms of microbubbles are needed compared to milligrams for other molecular imaging modalities such as MRI contrast agents.

Targeting strategies for microbubbles are versatile and modular.

Active targeting can be increased (enhanced microbubbles adhesion) by Acoustic radiation force using a clinical ultrasound imaging system in 2D-mode and 3D-mode.

Microbubbles don’t last very long in circulation. They have low circulation residence times because they either get taken up by immune system cells or get taken up by the liver or spleen even when they are coated with PEG.

Ultrasound produces more heat as the frequency increases. Monitering Required.

Microbubbles burst at low ultrasound frequencies and at high mechanical indices (MI), which is the measure of the acoustic power output of the ultrasound imaging system. Increasing MI increases image quality, but there are tradeoffs with microbubble destruction. Microbubble destruction could cause local microvasculature ruptures and hemolysis.

Disadvantages of CEUS

Targeting ligands can be immunogenic, since current targeting ligands used in preclinical experiments are derived from animal culture.

Low targeted microbubble adhesion efficiency. This is main reasons that targeted contrast-enhanced ultrasound remains in the preclinical development stages.

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