Ultrasound contrast media

Definition and Medical Role

Ultrasound contrast media, also referred to as ultrasound contrast agents (UCAs), are diagnostic agents administered to enhance echogenicity during ultrasonography. Unlike contrast agents used in CT (iodinated) or MRI (gadolinium-based), UCAs work by increasing acoustic reflectivity and signal intensity in targeted tissues or vascular structures without ionizing radiation or magnetic properties. They are used primarily in echocardiography, liver imaging, kidney perfusion, and increasingly in non-cardiac vascular imaging.

Ultrasound contrast agents typically consist of gas-filled microbubbles encapsulated in a lipid, protein, or polymer shell. These microbubbles remain within the vascular compartment (intravascular contrast), providing real-time visualization of blood flow and tissue perfusion.

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Mechanism of Action

Ultrasound contrast media enhance ultrasound imaging through the following principles:

1. Microbubble Formation
   – Agents contain inert gases (e.g., sulfur hexafluoride, perflutren) in microbubble form.
   – The gas core reflects ultrasound waves strongly due to its acoustic impedance mismatch with blood/tissue.

2. Acoustic Resonance
   – When insonated with low mechanical index (MI) ultrasound, microbubbles oscillate non-linearly, emitting high-frequency harmonics that can be selectively captured, increasing contrast.

3. Intravascular Localization
   – Microbubbles remain in the circulation and do not cross capillary membranes, making them ideal for vascular imaging.

4. Rapid Clearance
   – The gas is eliminated via the lungs, and shell components via liver and kidneys, ensuring a short half-life and safety.

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Types of Ultrasound Contrast Agents

Ultrasound contrast agents are typically categorized by the composition of their gas core and shell:

• Gas Core:
  – Sulfur hexafluoride (e.g., SonoVue)
  – Perflutren (e.g., Definity, Optison)
  – Nitrogen or air (older agents)

• Shell Composition:
  – Phospholipids (most modern agents)
  – Albumin (e.g., Optison)
  – Synthetic polymers (e.g., early agents)

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Indications and Clinical Applications

Ultrasound contrast agents are used in:

1. Cardiology

   • Left ventricular opacification in suboptimal echocardiograms

   • Detection of cardiac masses or thrombi

   • Myocardial perfusion imaging

2. Abdominal Imaging

   • Characterization of focal liver lesions (e.g., hepatocellular carcinoma vs. hemangioma)

   • Detection of liver metastases

   • Kidney perfusion and tumor vascularity

   • Evaluation of pancreas and spleen lesions

3. Pediatric and Urologic Use

   • Vesicoureteral reflux (contrast-enhanced voiding urosonography, ceVUS)

   • Congenital urinary anomalies

4. Vascular Imaging

   • Contrast-enhanced ultrasound (CEUS) for carotid arteries, aorta, peripheral vascular disease

5. Interventional Procedures

   • CEUS-guided biopsies and ablation therapy

   • Tumor follow-up and response evaluation

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Generic Names of Approved Ultrasound Contrast Media

Brand Name	Generic Name / Active Agent	Shell Type	Approved Use
SonoVue® / Lumason® (US)	Sulfur hexafluoride lipid-type A microspheres	Phospholipid shell	Echocardiography, liver imaging, CEUS
Definity®	Perflutren lipid microspheres	Phospholipid shell	Left ventricular opacification, perfusion
Optison®	Perflutren protein-type A microspheres	Human albumin shell	Echocardiography
Sonazoid®	Perflubutane microbubbles	Phospholipid shell	Liver lesion characterization (Asia)
Levovist® (withdrawn)	Galactose-based microbubbles with air	Galactose shell	Older generation (Europe, now obsolete)

Detailed Pharmacological Profiles

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1. Sulfur Hexafluoride (SonoVue / Lumason)

• Structure: Microbubbles of sulfur hexafluoride gas encapsulated in a phospholipid shell

• Administration: IV bolus or infusion

• Dose: Typically 2.4 mL per injection (can be repeated)

• Elimination: Gas exhaled via lungs; shell metabolized in liver

• Indications:

  • Echocardiography (improved endocardial border definition)

  • Liver CEUS (differentiation of benign/malignant lesions)

  • Pediatric vesicoureteral reflux (off-label in some regions)

• Adverse Effects:

  • Headache, nausea, injection site pain

  • Rare anaphylactic reactions (hypersensitivity)

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2. Perflutren Lipid Microspheres (Definity)

• Structure: Perflutren gas with phospholipid shell

• Administration: IV bolus (1.3 mL) or continuous infusion

• Activation: Vial requires mechanical activation (shaking) prior to use

• Indications:

  • Suboptimal echocardiography

  • Left ventricular cavity opacification

  • Detection of cardiac masses

• Precautions:

  • Caution in patients with pulmonary hypertension

  • Transient back pain or chest discomfort may occur

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3. Perflutren Protein Microspheres (Optison)

• Structure: Perflutren gas in a human serum albumin shell

• Use: Echocardiography only

• Features:

  • Ready-to-use suspension (no activation)

  • May be used in mechanically ventilated patients

• Warnings:

  • Contraindicated in right-to-left cardiac shunts or hypersensitivity to albumin

  • Risk of serious cardiopulmonary reactions in rare cases

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4. Perflubutane Microbubbles (Sonazoid)

• Structure: Perflubutane gas microbubbles in phospholipid shell

• Unique Feature: Phagocytosed by Kupffer cells in liver → prolonged enhancement

• Use:

  • Differentiation of hepatocellular carcinoma vs. benign lesions

  • Liver-specific CEUS applications

• Status:

  • Approved in Japan, Korea, parts of Europe

  • Not approved in the US as of 2025

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Dosage and Administration

Agent	Typical Dose	Route	Repeatability
SonoVue / Lumason	2.4 mL IV bolus (up to 3 doses)	Intravenous (IV)	Yes, up to 3 injections
Definity	1.3 mL IV bolus or infusion	IV bolus or infusion	Yes, monitor cardiopulmonary status
Optison	0.5 mL IV (can repeat)	IV bolus	Yes
Sonazoid	0.015 mL/kg IV	IV bolus	Once per exam

Adverse Effects and Safety Considerations

• Common Reactions:

  • Nausea, flushing, dizziness, injection site irritation

• Serious Adverse Effects:

  • Hypersensitivity and anaphylactic reactions

  • Pulmonary hypertension exacerbation

  • Rare: arrhythmias, chest pain, back pain

• Monitoring:

  • Vital signs during administration

  • Post-injection observation for 30 minutes in at-risk patients

• Contraindications:

  • Known allergy to any component (especially albumin-based agents)

  • Right-to-left cardiac shunts

  • Uncontrolled hypertension (caution)

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Special Populations

• Pregnancy: Limited data; use only if clearly indicated (usually avoided)

• Children:

  • Lumason/SonoVue approved in some countries for pediatric VUR imaging

  • Others are off-label in pediatric populations

• Elderly: Generally safe with standard precautions

• Hepatic/Renal Impairment: No dose adjustment typically needed; not nephrotoxic

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Drug Interactions

Ultrasound contrast agents are generally not systemically bioactive, so no significant drug–drug interactions have been identified. However:

• Avoid mixing with other drugs in the same IV line

• Do not co-administer with high-pressure injections to prevent microbubble collapse

• Avoid concurrent use with nitroglycerin in acute cardiac assessments (potential hypotension)

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Advantages of Ultrasound Contrast over CT/MRI Contrast

Parameter	Ultrasound Contrast	CT Contrast	MRI Contrast
Nephrotoxicity	None	Nephrotoxic	Less nephrotoxic
Radiation exposure	None	Yes	None
Portability	Bedside (yes)	Limited	Limited
Cost	Lower	Higher	High
Real-time imaging	Yes	No	Limited
Vascular specificity	High	Moderate	Moderate

Emerging Applications

• Targeted molecular imaging: Attaching ligands to microbubbles for tumor or vascular target binding

• Drug delivery platforms: Using microbubbles to carry therapeutic agents and deliver via ultrasound activation

• Inflammatory marker imaging: Experimental use in detecting inflamed plaques or thrombi

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Regulatory and Commercial Status (2025)

Agent	FDA Approval (US)	EMA Approval (EU)	Other Notes
Lumason (SonoVue)	Yes (cardiac, liver)	Yes	Also CE-marked for VUR in pediatrics
Definity	Yes	Yes	Available in >50 countries
Optison	Yes	Yes	Restricted in severe albumin allergy
Sonazoid	No	Yes (select regions)	Widely used in Japan and Korea