Cardiovascular – Heart

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Contrast-enhanced ultrasound (CEUS) can dramatically improve the detection of coronary artery disease and stratify risk of heart attack or stroke.

CEUS is safe, accurate, completely avoids exposure to ionizing radiation, and can change patient outcomes and save lives. In addition, by salvaging non-diagnostic ultrasound examination, CEUS can help avoid unnecessary downstream tests and lower overall health care costs. Further, like conventional ultrasound examinations, CEUS is portable and easily accessible in a variety of clinical settings, provides real time diagnostic information that can speed access to appropriate therapy, and may improve workflows and efficiencies.

CEUS uses ultrasound contrast agents (UCAs), also known as ultrasound enhancement agents, to improve the clarity and reliability of conventional ultrasound scans. UCAs are comprised of liquid suspensions of biodegradable gas-filled microspheres (sometimes called “microbubbles”). When they are injected into a patient’s arm vein during an ultrasound exam, they flow through the body’s microcirculation without impediment, and are metabolized and expelled from the body within minutes.

Unlike agents used for other types of medical imaging, UCAs do not contain dye or present a risk of kidney damage.

UCAs are now integral components of ultrasound imaging throughout the world, and are approved for use in adult and pediatric imaging by the US Food and Drug Administration, the European Medicines Agency, and their counterparts in Asia, the Americas and elsewhere.

FDA-approved cardiac applications are limited to evaluation of the left ventricle of the heart and endocardial borders. However, CEUS scans may have significant diagnostic value with no added safety risk when used off-label during cardiac stress echocardiography and perfusion imaging studies. The Intersocietal Accreditation Commission guidelines for accrediting adult echocardiography laboratories requires the use of an UCA during stress echocardiography under certain specified conditions.

Under certain circumstances, CEUS may be superior to nuclear imaging or conventional ultrasound without a contrast agent. Nuclear scans generally have poorer spatial and temporal resolution and expose patients to ionizing radiation.

The following objectives and protocols reflect clinical CEUS practice in many medical centers throughout the world.

Objective of the CEUS study

To provide the highest quality 2D ultrasound images of the cardiac anatomy using ultrasound contrast agents (UCAs), sometimes also known as ultrasound enhancement agents. Real-time CEUS images help detect and stratify risk of cardiovascular disease by:

  • improving the detection of coronary artery disease and cardiomyopathies,
  • increasing endocardial border delineation and improving regional wall motion analysis,
  • generating left ventricular opacification to better quantify left ventricular volumes and ejection fraction, and
  • demonstrating microvascular perfusion

at rest and during stress echocardiograms.

The use and dosage of UCAs will be determined by the cardiologist staffing the procedure, or as per departmental protocol. UCAs will be administered by a physician, qualified sonographer or registered nurse.

Bolus administration generally reduces imaging time but results in higher UCA concentrations, so attenuation artifacts may be seen. Very low doses with slow saline flushes (5-10 ml slow normal saline flush over a period of at least five seconds) are recommended. Continuous infusions may provide prolonged and consistent enhancement with fewer attenuation artifacts.

Instrumentation and settings

Fundamental non-linear multi-pulse imaging is preferred over harmonic imaging, and a very low mechanical index (<0.2) will avoid destruction of the microspheres. The transmit focus may require adjustment, with setting at the apex to visualize apical thrombus, wall motion or perfusion, but otherwise should be positioned at the mitral annulus to visualize leaflet insertion for tracing LV/LVEF.

Protocol: Bolus administration during rest or stress echocardiogram

  1. Use small doses for resting or stress echocardiograms. Suggested doses are as follows:
    • Definity/Luminity (Lantheus Medical Imaging) – 0.1 ml
    • Lumason/SonoVue (Bracco) – 0.3-0.5 ml
    • Optison (GE Healthcare) – 0.3-0.5 ml
    Although higher doses may be necessary, start with lower doses to avoid shadowing/attenuation and waste of the UCA. Dosing is adjusted according to adequacy of visualization of the UCA in the cardiac chambers.
  2. Use a very slow saline flush via syringe (approximately 3-5 ml over at least 5 seconds; stop flushing when the UCA appears in the right ventricle), or use a saline drip, adjusting the rate as required to obtain a good image.
  3. For exercise stress studies, the UCA bolus and flush should be administered approximately 30 seconds before termination of exercise. For pharmacologic stress studies, the UCA bolus and flush can be administered through the same IV line as the pharmacological stressor at time of peak stress.
  4. Never flush vigorously because doing so will destroy the UCA microbubbles.
  5. Set up the ultrasound system to utilize contrast presets. The VLMI (very low mechanical index, MI= 0.1-0.2) fundamental non-linear multi-pulse imaging technique, such as amplitude modulation or combined amplitude/phase modulation, is preferred for BOTH optimal left ventricular opacification (LVO) and perfusion imaging. Alternatively, second harmonic LMI (low mechanical index, MI= 0.2-0.3) imaging can be used, but this is less optimal and will achieve only LVO.
  6. Acquire images when:
    • For LVO: Homogenous left ventricular cavity contrast without swirling in the apex or shadowing of basal segments is seen. (As previously described, this is best achieved with a fundamental non-linear multi-pulse imaging technique such as amplitude modulation or combined amplitude/phase modulation.) Near and far field time gain compensation adjustments may be needed, and transmit focus may need to be adjusted. Repeat UCA bolus and flush as needed to maintain optimal visualization.
    • For perfusion: Proceed as above, with additional step of using high mechanical index (high MI) “flash” impulse, which will destroy the UCA within the myocardium, without evidence of LV cavity destruction. The high MI flash frame number and/or flash frame mechanical index can be adjusted to achieve UCA destruction within the myocardium without causing loss in the LV cavity. Normal myocardial perfusion: Normal myocardial perfusion is indicated by complete replenishment of myocardial contrast within five seconds of the high mechanical index (MI) impulse under resting conditions, and within two seconds under stress conditions. Abnormal myocardial perfusion: Abnormal myocardial perfusion is indicated by delayed or absent replenishment after flash high MI impulses, and may be subendocardial or transmural in distribution.

Protocol: Continuous infusion during rest or stress echocardiogram

The following protocol should be used for continuous infusion of the UCA, bearing in mind that the UCA may be degraded by small caliber intravenous cannulae. Accordingly, 20 G needles or larger are recommended (although 22 gauge needles have been used). See package inserts for additional details. In addition, for both bolus and continuous infusions, cannulation of an antecubital vein rather than a hand vein is preferred because the UCA delivery site is nearer the heart.

Definity/Luminity must be activated by agitating the vial for 45 sec in a specific Vial Mix device, and then withdrawn from the vented vial. Dilution of the contents of one Definity/Luminity vial into 29mL 0.9NS to make a total of 30ml Definity®/Luminity. (Do not mix until just prior to infusion; if unused more than 5 minutes, rock the IV bag gently to assure even distribution of the microspheres.). The recommended infusion rate is 3-6 ml per minute. Intermittent slow agitation is recommended to maintain microbubble suspension.

Lumason/SonoVue may be prepared according to instructions on the package insert and administered as an infusion. In Europe, SonoVue may be administered via a custom-designed pump that continuously oscillates to agitate the agent; the pump is not currently available in North America. Lumason/SonoVue is aspirated from the vial into a 20ml syringe, which is then placed inside the pump and an infusion line is connected to the syringe. The pump oscillates for 90s during which time the suspension of the agent is mixed. The pump continues to oscillate after initial mixing is complete. The infusion rate can be controlled via the touchpad and increased or decreased as necessary; as the rate is increased or decreased, the time remaining for agent use is displayed and simultaneously shortens / lengthens (respectively).

Optison may be administered as an infusion by using approximately 1.5 ml diluted in 20 ml normal saline, filling the IV line with Optison or flushing the Optison in via saline (infusion pump or Dial-A-Flow). The flow rate may be adjusted to visualize endocardial borders. The IV line should be shaken gently and tapped to prevent Optison from sticking to the sides or separating.

Procedure for continuous infusion

  1. Make 2 syringes – One for REST, one for STRESS (if stress test is utilized).
  2. Adjust dose to achieve the following image appearance of the left ventricle from the apical windows:
    • For LVO: Homogenous left ventricular cavity contrast without swirling in the apex or shadowing of basal segments. This is best achieved with a fundamental non-linear multi-pulse imaging technique such as amplitude modulation or combined amplitude/phase modulation.
    • For LVO with perfusion: Homogenous myocardial contrast opacification in all segments with normal wall thickening (using near and far field time gain compensation adjustments), and adjustment of transmit focus.
    • Complete disappearance of myocardial contrast following high mechanical index “flash” impulses (0.8-1.0 mechanical index (MI), 5-20 frames) with minimal evidence of cavity destruction (adjusting the flash frame number and/or flash frame mechanical index (MI)).
    • Normal myocardial perfusion: Complete replenishment of myocardial contrast within five seconds of the high mechanical index impulse under resting conditions, and within two seconds under any type of stress (exercise, dobutamine or vasodilator), is consistent with normal perfusion.
    • Abnormal myocardial perfusion: Findings other than this would be considered abnormal perfusion. Attenuation must be ruled out if any delay is confined to just basal segments in apical windows. The apical windows can be purposefully foreshortened to bring these basal segments into the near field for better evaluation should attenuation be suspected. In addition, the image plane can be adjusted to bring the myocardial segments of interest nearer to the center of the image, rather than at the sides where contrast sensitivity is lower. Near field time gain compensation should be adjusted higher for most systems to avoid the appearance of decreased apical segment contrast enhancement. This should be optimized under resting conditions.
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