Contrast Agents

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Definition

Contrast agents [1] are air or gas-filled microbubbles with a stabilizing shell constituted by macromolecules: carbohydrates, phospholipids, proteins. Ultrasound contrast agents are administered by intravenous injection as a bolus or as a continuous infusion and are confined to the vascular space (blood-pool agent). Nowadays ultrasound contrast agents are mainly used in association with contrast dedicated technologies, which are able to highlight the bubbles signal inside the parenchymal microcirculation.

History

The earliest report on contrast agents in ultrasound imaging dates back to 1968. The first investigations used air-filled microbubbles, which were highly unstable, dissolved rapidly in blood and lost their echogenicity; furthermore, significant amounts were filtered by the lungs because of their large diameter. The first commercial contrast agents were developed by sonication of 5% human albumin solution and became commercially available in Europe in 1991 first as Echovist (Berlex, Lachine, QuebecCity, Canada). In 1996, Levovist appeared on the market (Bayer Shering, Berlin Germany). In the United States, Albunex (Mallinckrodt, St. Louis, Missouri) was introduced in 1994. A second generation of contrast agents was developed; the air in the bubble was changed to higher-molecular-weight gases which resulted in more stable bubbles. SonoVue, Optison, and Luminity (marketed in North America as Definity) are the main representatives of this group (Table 1). These microbubbles do not aggregate, are biologically inert and safe. The most widely used in Europe is SonoVue, whilst Optison and Definity are more frequently used in the United States.

Table 1. Contrast agents in United States and Europe

AGENT MANUFACTURER ACTIVE SUBSTANCE SHELL APPROVED
SonoVue Bracco Imaging Sulphur hexafluoride Surfactant/powder EMEA
Optison GE Healthcare Perflutren Albumin FDA/EMEA
Definity/Luminity† Lantheus Medical Imaging Perflutren Lipids FDA/EMEA

†Luminity has been approved (EMEA) but marketing authorization suspended (not available)

Approved indication for European Medicines Agency

Apical thrombus
The indications have been developed starting from the concept that up to 15% of patients affected by obesity and chronic obstructive pulmonary disease are technically difficult to image, which results in reduced image quality and lower diagnostic accuracy. This percentage is as high as 30% in critically ill patients [2] and 33% in patients undergoing stress echocardiography.

Thus, contrast agents are approved to be used for the improvement of left ventricular endocardial border delineation and opacification of the left ventricle in following cases:

  • Improve assessment of global cardiac function: increase the accuracy of calculation of left ventricular end-systolic, end-diastolic and volumes and ejection fraction. It should be used when study without contrast enhancement is inconclusive or suboptimal (at least two contiguous segments in the 4- or 2-chamber view of the ventricular border were not evaluable)
  • Increase assessment of regional wall motion and consequently improve the detection/exclusion of ischemia at rest and at peak stress condition. Non-diagnostic stress echos due to insufficient image quality are not acceptable in contrast agents era
  • Improve the identification of cardiac mass inside the cardiac chambers: thrombus, tumor
  • Confirm or exclude the echocardiographic diagnosis of the following left ventricular structural abnormalities, when non-enhanced images are suboptimal for definitive diagnosis: apical hypertrophic cardiomyopathy, ventricular non-compaction, ventricular pseudoaneurysm

SonoVue ® (authorisation date 26/03/2001) is the only approved for another vascular indication that is Doppler signal improvement of macrovessels (cerebral arteries, extra-cranial, carotid and peripheral arteries) and microvessels (vascularity of liver and breast lesions leading to more specific lesion characterization). SonoVue is contraindicated in Europe for use in patients with recent (<7 days) acute coronary syndrome or clinically unstable ischaemic cardiac disease. This came from a ‘‘black box warning’’ issued by the US Food and Drug Administration in October 2007 for the commercially available ultrasound contrast agents after reports of serious adverse events that occurred in close temporal relationship to contrast administration. All companies developed a comprehensive risk management strategy to more clearly define the safety profile and finally obtained the modification of boxed warnings. Sonovue’s marketing authorization has been submitted to FDA and it will be likely available in United States within next few years.

Normal myocardial perfusion
The authorisation date of Optison ® and Luminity ® is 18/05/1998 and 20/09/2006, respectively.

It is well-known that ultrasound contrast agents are not yet approved for myocardial perfusion imaging, although the benefit of this application is increasingly recognized [3] [4].

Nevertheless, at the beginning of July 2012 Acusphere, Inc. announced that it had completed the Marketing Authorisation Application dossier for Imagify™ (Perflubutane Polymer Microspheres) and is now starting the process of filing the Marketing Authorisation Application dossier with the European Medicines Agency to support the regulatory review of Imagify in the European Union for perfusion assessment

References

  1. Chelliah RK, Senior R. Contrast echocardiography: an update. Curr Cardiol Rep. 2009;11:216-24
  2. Cosyns B, Roossens B, Hernot S, El Haddad P, Lignian H, Pierard L, Lancellotti P. Use of contrast echocardiography in intensive care and at the emergency room. Curr Cardiol Rev. 2011 Aug 1;7(3):157-62.
  3. Senior R, Shah BN. Myocardial contrast echocardiography for simultaneous assessment of function and perfusion in real time: a technique comes of age. Circulation. 2012 Aug 7. [Epub ahead of print]
  4. Gaibazzi N, Reverberi C, Lorenzoni V, Molinaro S, Porter TR. Prognostic value of high-dose dipyridamole stress myocardial contrast perfusion echocardiography. Circulation. 2012 Aug 7. [Epub ahead of print]

Further reading

Senior R, Becher H, Monaghan M, et al. Contrast echocardiography: evidence-based recommendations by European Association of Echocardiography. Eur J Echocardiogr. 2009;10:194-212.

External links

http://www.emea.europa.eu/ema/ http://www.icus-society.org/

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