Contrast-Enhanced Ultrasound (CEUS) - HD

Introduction

Good afternoon.

My name is Steve Feinstein.

I'm a professor of medicine at Rush University Medical Center in Chicago.

And the topic I'll be speaking about today is a review of contrast enhanced ultrasound.

This slide is a citation from Daniel Burnham.

After the Chicago fire in 1871, Daniel Burnham stated, make no little plans.

They have no magic to stir a men's blood.

The review of contrast ultrasound should be in keeping with Daniel Burnham's statement.

That is, it will stir your blood.

Why Contrast Ultrasound is a Resurgent Field

Contrast ultrasound is really now at a confluence of events and as stated on the slide, it is US time or ultrasound time.

In the center you see ultrasound imaging and therapy using contrast enhanced techniques.

Why is this now a resurgent field?

There are safety concerns with the radiation medicine is becoming more institutional based, particularly on healthcare reform.

As noted, there will be reduced reimbursement for over utilization of some perhaps big box imaging modalities such as PET CT and mr.

But the times are changing too as the imaging is changing.

So are the clinical disease states.

There's been a significant reduction in cardiovascular death since 1980, approximately 50% reduction and 26 since 1999.

As noted on these slides, particularly reduction in ST elevation MI is that due in fact to the prominence of early detection and screening and a corp?

Accompanying with this reduction in interventions is a reduction in payments to hospitals and medical groups.

Accordingly, there is now a new awareness of the radiation and the exposure risk for long-term cancer.

And now the advance of ultrasound contrast applications,

Citation from Circulation 2009

A citation from circulation 2009.

This was from a scientific advisory from the American Heart Association Committee on Cardiac Imaging of the Council on Clinical Cardiology and the Committee on Cardiovascular Imaging and Intervention of the Council on Cardiovascular Radiology and Intervention.

As you'll note in the first bullet point, the collective dose of ionizing radiation with medical imaging has increased over 700%.

The second bullet point is the takeaway message.

Physician education should emphasize that cardiac imaging studies that expose patients to ionizing radiation should be ordered only after thoughtful consideration of the potential benefit to the patient and in keeping with established appropriateness guidelines or criteria.

This slide documents the increasing and now decreasing use of CT scans in children in the us.

This was taken from cardiac imaging article may Rise Raise cancer.

This is from February 7th, 2011.

Clinical Applications of Contrast Enhanced Ultrasound

What are the clinical applications of contrast enhanced ultrasound?

Number one, it reduces risk.

It reduces downstream testing, reduces ionizing radiation and there is no nephrotoxicity.

The use of contrast makes the ultrasound images more accurate and reliable.

It does reduce healthcare costs, it saves lives and it has an international acceptance in cardiac and non-cardiac or whole body imaging throughout the world.

Imaging Delivery Vehicles

Imaging deliver delivery vehicles as noted on this slide, the ultrasound contrast agents rapidly pass through the capillary vessels in the upper video.

In the lower video. This is a single ultrasound microsphere examined at around 20 million frames a second.

So overall the microspheres are near perfect intravascular tracers with a mean size of 2.2 to four microns, three to 500 million microspheres per cc.

Value in Cardiac Imaging

What is the value?

Well, as you can see from this video, this is an apical four chamber of the cardiac left ventricle of a patient.

Now you can see the contrast agent once administered, administered intravenously pacifying the entire left ventricular chamber.

What was gained from a half cc of an intravenous injection is a clear identification of the chamber, endocardial surfaces and wall motion activity.

Contrast enhanced ultrasound is used in particular for left ventricular opacification.

The pre contrast image on the left is from an apical four chamber still frame, and on the right post contrast knows that the entire endocardial surface is well delineated and in fact, following the guidelines, if two or more contiguous segments cannot be identified of the endocardial surface of the left ventricle contrast is indicated.

The post contrast or right still frame image identifies that all six sub endocardial regions now are clearly identified.

After contrast in the first case, this is a 60-year-old woman seen in the intensive care unit with sympathomimetics and Lasix.

If you notice her left ventricular chamber highlighted in the middle of the video is poorly identified but appears to be contracting very weekly following the intravenous administration of a half cc of a contrast agent.

Notice that the left ventricular function is actually hyperdynamic, not hyperdynamic, leading to increased diagnostic accuracy and alteration in her therapy.

The next case is a 66-year-old man who was seen for a retu re re, uh, for a return for a defibrillator check.

His ejection fraction was approximately 30% and the defibrillator was used to prevent sudden death.

In the image. You'll notice that the ventricle is difficult to identify.

The endocardial surfaces are not well seen.

The pacemaker lead can be seen in the right ventricular chamber of this apical four chamber view.

This patient, due to the poor quality of the image qualifies for ultrasound contrast enhancement.

The next frame shows after the contrast was injected, the entire endocardial surface of the left ventricle is well identified, but notably there is a mass in the apex area consistent with a thrombus.

This is notable in that the patient has an wall motion abnormality in the apex consistent with a previous myocardial infarction.

A zoomed picture of the same image reveals that the thrombus is attached to the wall of the apex and contrast can actually be seen swirling around the contra, around the thrombus showing the stalk of the thrombus.

Stress Echocardiography with Contrast

The next slide describes the Ontario Health Technology Assessment.

This is from Canada.

In the year 2010, the topic was stress echocardiography with contrast for the diagnosis of coronary artery disease.

It was an evidence-based analysis.

23 observational studies were reviewed.

The bullet points include stress echo with contrast has a higher diagnostic accuracy in the diagnosis of coronary disease than stress.

Echo without contrast stress ECHO has a similar diagnostic accuracy to SPECT imaging.

The addition of contrast in patients with suboptimal echos significantly improves results and there is no statistically significant higher mortality in patients who receive contrast compared to those who do not stress.

Echocardiography is a mainstay of contrast enhanced imaging.

As you can see from this video frame, the first image shows contrast entering the right ventricle, passing through the lungs, and now entering into the left ventricular chamber.

This is at baseline so the images can be assessed for wall motion and wall thickening.

Once the exercise has begun, the four chamber quad screen is identified and the baseline images are on the left with the peak images on the right showing the similar LV opacification at baseline and rest.

The final image reveals an ultrasound enhanced contrast perfusion imaging of the ventricle.

Notice that the ventricle muscle itself is orange and the chamber is yellow highlighting the perfusion of the muscle while seen in this still frame safety of contrast agents.

Safety and Endorsements

This meta-analysis describes the benefits of contrast by combining multiple independent studies.

Note on the odds ratio on the far right, the use of contrast favors experimental use or that of contrast versus the control, no contrast.

So indeed the use of contrast is not associated with adverse event and in fact is beneficial.

Professional societies have endorsed the use of contrast enhanced ultrasound on an evidence-based medicine design.

The first acceptance is the American Society of Echocardiography.

The consensus statement both in the year 2000 and 2008 recommended the use of ultrasound contrast for left ventricular opacification when two or more contiguous segments were not well identified.

Subsequently, the American College Cardiology, the American Heart Association, the European Association of Echo, the IAL, which is now the IAC, the Ontario Health Technology Assessment has endorsed the use of contrast for appropriate indications.

And finally, the appropriateness guidelines for the use of contrast published in 2011 indeed endorsed the use of contrast.

As indicated above, most most impressive study was published in JACC as an expedited study by the senior author Kurt in 2009.

The summary of their results revealed that the use of contrast enhanced ultrasound benefited patients throughout the hospital, be it inpatient, outpatient, or even in the sickest uh, intensive care units such as MICU and SICU.

All patients benefited from contrast in the sense that procedures were avoided.

There was a medication change or both.

Notably in those patients in the surgical intensive care unit, roughly two thirds of the patients benefited from the use of contrast.

The results of their study revealed that uninterpretable studies were reduced from 11.7% to 0.3%.

Importantly, therapeutic decisions were changed 10.4%.

A single important observation from their study was that left ventricular thrombo were detected in 35 patients and were considered to be definite in three before contrast usage.

After contrast usage, only one patient actually had a suspected thrombus, but there were five new ones.

There is a cost benefit savings to the use of contrast as identified in the second bullet point.

And the third point is what we have stated.

The appropriate use of contrast improves outcomes to jump from cardiology to whole body imaging.

We'll briefly review.

There are many other applications for the use of contrast enhanced ultrasound, which can be seen on this slide depicting the carotids, cardiac chambers, coronary arteries, liver, kidney, and the aorta.

Applications in Vascular Imaging: Carotid Arteries

In this particular view, this is a cartoon example of a carotid artery.

The common artery is on the right, the bifurcation in the middle and the external and internal carotid can be seen.

We now go to a clinical case of a contrast ultrasound exam.

This is a longitudinal view of carotid artery now filled with a half CCC of intravenous contrast and you'll note there's an ulcer as well as lumen opacification.

This view is actually a normal study identifying a lumen that is normal without plaque and an IMT that is equally normal.

The study, uh, courtesy of Hans Peter Wescott from Hanover, Germany demonstrates a plaque with both positive and negative remodeling filled with ultrasound contrast in its borders.

Once a plaque is removed, the histology reveals that there's often a core of the carotid atherosclerosis that's necrotic, but inside the plaque itself are many layers of micro vasculature or the vasorum.

These angiogenic vessels are immature and often rupture leading to hemosiderin deposits or blue staining with prussian blue as can be seen in the lower right column.

Therefore, these angiogenic vessels lacking parasites actually rupture leaving iron deposits as a permanent stain of an intra plaque rupture.

Furthermore, these plaques demonstrate marked angiogenic angiogenesis growth as can be identified with a CD 31 stain, which is a mouse auto antibody to human endothelial cells.

And once again, the hemo citrin staining blue shows the intra plaque rupture throughout the plaque histology.

Atherosclerosis is not the only inflammatory disease that one can use.

Contrast enhanced ultrasound to look at angiogenesis within the walls of the artery in this patient from professor at Masery and Stefano Colley in Milan note the intense opacification of the lining of the carotid artery filled with angiogenic vessels Con uh, contrast that study with one from uh, Maria Fabrizio in Rome.

The plaque in this case is very large, but absent much angiogenesis and the final carotid image will reveal a small plaque at the base of the bifurcation that appears to be quite angio, genetically filled with vessels which indicates more instability versus one that is more fibrotic.

This Seminole paper from Hellings in 2010 looked at the composition of carotid plaques associated with future cardiovascular events.

Approximately 800 patients were followed prospectively major events were monitored such as heart attack, stroke, and death.

It turned out that the authors looked at what they felt were the highest risk plaque indicators such as lipid, core calcification, smooth muscle macrophages, intra plaque vessels and plaque hemorrhage.

And indeed the only two factors that seemed to indicate a vulner plaque leading to a cardiovascular event, heart attack, stroke, or death ended up with plaque hemorrhage or vessel density.

None of the other markers by histology indicated or predicted cardiovascular events.

Their conclusion was, it was actually the first pros prospective study looking at the histologic composition of a plaque to determine outcome.

The re, they reported the presence of plaque hemorrhage and vessel density or independently associated with risk of future events.

Is the angiogenesis identified in the carotid artery localized to the carotid or is there a systemic signifying event?

In fact, the journal of circulation from Japan used contrast enhanced ultrasound to identify the angiogenesis of the carotid arteries and correlated that to the severity and instability of coronary disease in patients.

This was published in 2013.

Furthermore, the vascular surgeons from Europe have now used contrast to look at arterial disease and in fact, from their work concluded, there will be a paradigm shift from plaque anatomy and structure to actual physiology and biology.

Using contrast enhanced ultrasound, there is a possibility of imaging plaque microvasculature a proven hallmark of vulnerability.

In this brief video, we will show you a 3D reconstructed carotid image with contrast as shown in the earlier cross-section.

We now can show you a longitudinal view in 3D.

And is this a useful tool for the future to look at early angiogenic disease in young patients?

This is a young patient with diabetes who demonstrated significant adventitial fasor due to the onset of diabetes.

Other Applications: Renal and Catheter-Based Imaging

Where else can we use contrast to look at atherosclerotic disease?

Well, certainly renal perfusion imaging, this is a half cc of contrast injected intravenously, completely pacifying the renal bed of vascularity in this patient.

And can we in the future use a catheter based tool without in ionizing radiation to follow through the venous and arterial system using contrast as an dye?

This is a good example of ultrasound based catheter usage for angiography and ultimately besides a diagnostic improvement, the ultrasound contrast agents have been and are going to be used as delivery systems for drugs and genes.

Future Directions: Ultrasound Directed Therapy

The unique opportunity to perform a site specific ultrasound directed delivery system will be realized in the future why ultrasound directed therapy is not viral based.

It uses already approved FDA microspheres for imaging.

The payload on these microspheres is basically unlimited.

The target organs are anywhere in the body that one can use ultrasound safely.

And none of the proposed opportunities to use naked DNA are insertional in their designs.

Specifically, the targets published now in the literature include cardiovascular, metabolic cancer, brain disorders, stem cell therapies, and others more will be developed in time.

Conclusion

The final slide is the International Contrast Ultrasound Society.

This is our website.

This is the annual conference, and I thank you very much for your attention.