Off Label, Not Off Limits: How You Can Use CEUS in Your Practice Today - HD

Introduction

Hi, I'm Richard Barr.

I'm in private practice in Youngstown, Ohio.

Today I'd like to give a lecture on doing off-label use of ultrasound contrast in the United States.

Today I'd like to give a talk mostly for the audience from the United States, off-label, but not off limits.

How can we use ultrasound contrast in our practice today?

Most people know that ultrasound contrast has not been approved by the FDA for use in the abdomen in the United States, but it is approved for use in cardiology.

As physicians, we are able to do contrast ultrasound in the abdomen off-label.

I think many people actually every day do off-label uses in CT and MR in their practice and don't even realize it.

I think there are a lot of really good applications to use contrast ultrasound in our practices to really help our patients.

I'd like to go over that today and give you an outline as to how you can get started in using ultrasound contrast in the United States.

We're talking about off-label use. It's not off limits.

We've been doing off-label contrast for over 10 years in our practice. The FDA has not come and locked me up yet.

What is Off-Label Use?

If a physician uses a product for an indication not in the approved labeling, they have the responsibility to be well-informed about the product to base its use on firm scientific rationale and on sound medical evidence.

To maintain records of the product's use and effects does not require an IRB if this is not being done for research.

I go over this in much more detail in an article that is in Journal of Ultrasound in Medicine.

The use of a marketed product in this manner, when the intent is the practice of medicine does not require submission of an investigational new drug application or IND, it does not require an investigational device exemption, an IDE or review by an institutional review board an IRB.

However, some institutions at which the product may be used under its own authority may require an IRB for review or other institutional oversight.

If you're not using this to do a research study, there is no FDA reason why you need to have a IRB approval.

What are Ultrasound Contrast Agents?

Just going briefly, what are ultrasound contrast agents?

These agents are a little gas filled lipoproteins.

They have a nonlinear response to the ultrasound beam, which allows the subtraction of other tissues, which have a linear response so that we can get a vascularity only image to look at, at very high mis the bubbles burst.

At very low mis the bubbles have this nonlinear fundamental and harmonic signals, which we can use to show in real time the vascular blood flow to the lesion.

Advantages of Ultrasound Contrast

There are several advantages to using ultrasound contrast.

We get a real time assessment of vascularity at very high frame rates.

These are true intravascular agents.

In a way, they do differ from CT and MR in that there is no extravasation.

Sometimes in later phases, we may get slightly different appearing images than we do in CT and MR.

There is no renal or liver impairment.

These are very short half-life medications, approximately a five minute window.

We can use multiple injections and there's no ionizing radiation.

Disadvantages of Ultrasound Contrast

The disadvantages to implementation of ultrasound contrast in a department is it does require an IV that you need two people as one needs to scan and one needs to inject the contrast agent.

There's lots of data and we usually save a three minute clip.

If you try to send this to your packs, your packs will probably crash.

What we do is we save the three minute clip to a external USB drive, and we go back through the clip and select images that we send to the packs, or we can take a very small clip and send it to the packs.

When to Consider Ultrasound Contrast

When should you consider ultrasound contrast to be used?

Ultrasound contrast for routine use should be considered when it can help a patient.

In cases that we find extremely helpful is the renally impaired patient that requires a contrast study.

If they cannot receive an MR or CT with contrast, ultrasound with contrast is a very good alternative.

Patients with a CT or MRI allergy contrast.

We've had several cases, particularly in liver cases, most commonly focal nodular hyperplasia where CT or MR do not answer the clinical question or give conflicting results or when it's really important to know if there's no flow present within a lesion such as after an RFA.

The ability of contrast enhanced ultrasound to subtract background signal really allows us to see very small amounts of blood flow within a lesion.

Clinical Applications

The type of exams that we routinely perform in our lab are livers.

Most of our cases are cases where the CT and MR give conflicting results.

This often happens with focal nodule hyperplasia.

We don't have the time to go over that. But if you look at some of the references we're going to give, you can see that contrast enhanced ultrasound is maybe the preferred method in evaluation and characterization of focal nodule hyperplasia.

Our biggest application is in the eval evaluation of indeterminate renal masses.

Our urologists feel that we perform much better than CT and mr and looking for blood flow, particularly in bosniac three lesions, we can see small blood flow in septations or irregularities in the septations that are very difficult to monitor in CT and MR with contrast, and I'll show you some of those examples shortly, also in aortic stent grafts.

Many of these patients have renal failure and cannot get or receive a contrast in MR. And ct. Our vascular surgeons find that we are a very good alternative to using those other methods.

We can use this in evaluation of small bowel for irritable bowel syndrome.

This I think is going to be a growing application.

We have other applications that come up where there are situations and other organs where CT and m or just do not answer the question, and our referring doctors refer a patient for ultrasound contrast to see if we can give some help.

There are ssom as well as world Federation of Ultrasound and Medicine Guidelines out.

I really recommend that if you're going to do these, that you get these guidelines.

They're extremely helpful in showing you how to perform an examination as well as where these applications are very useful clinically.

Examples from Case Studies

Let me just show you some of the examples that we have from our case studies.

When we do RFAs, we really prefer to use enhanced ultrasound to evaluate the ablated area.

Because as you can see in this case, if we do a good job and there's no blood flow, we actually have a large black hole.

It's very easy and very confidently you can say that there is no residual blood flow in this lesion where if we look at the same case on ct, the underlying soft tissue makes it very hard for us to determine if there is enhancement of this lesion.

In this case, we weren't even able to give contrast because of the patient's renal failure.

These are excellent applications for ultrasound with contrast.

This was an elderly gentleman that had an aorta iliac stent graft placed, was in renal insufficiency and was not able to obtain A-C-T-R-M-R with contrast.

The clinicians were following this patient actually with serial, non enhanced cts.

This actually is the same patient of the image I just showed you of the renal ablation.

When we brought the patient back to evaluate his renal ablation, we noticed that there was a large amount of contrast within the native aorta.

Here's our aortic stent, and we could actually see that there was actually a very large defect in the stent graft.

It was a type three endo leak.

The patient went on and had an angiogram which actually was as interpreted as a type two endo leak and was treated with glue embolization and the aneurysm the leak promptly reoccurred.

I think one of the things that's a really big advantage for us we're using the enhanced ultrasound is we have very high frame rates.

Even on angiography, this leak was so large that it went from no contrast in the native aneurysm to a large amount of contrast in the aneurysm.

It was very hard for them to determine exactly where the leak was.

We were able to even our video clip actually watch the bubbles come through here because of the high frame rate.

This is a patient that we did quite a long time ago and published a case report on.

This was an elderly gentleman that had a 20-year-old renal transplant that developed a transplant renal artery stenosis.

We had done an angiogram to confirm that and to place a stent to open up the stenosis.

When the angiogram was done, there was a blush in the kidney.

Which was flagged in our angiography partners suggested a follow-up study to exclude a renal mass.

The patient had both a enhanced CT and enhanced Mr which were normal even in retrospect.

Our urologist sent the patient to us for an enhanced renal ultrasound.

You can see there, there is a small markedly enhancing mass.

This is very early on in the arterial phase. We still don't have much cortical enhancement.

The interesting thing about this was we were only able to see this for several seconds in this early arterial phase, and then the lesion became isod dense to the remainder of the kidney.

This is why we didn't see this on the enhanced CT or enhanced MR because there was only a very small window of opportunity to see this lesion when it was enhancing.

The timing in the CT and MR was such that it was not visible.

Since we could only see this on enhanced ultrasound, we performed a radio frequency ablation using enhanced ultrasound to guide our needle placement.

Here we can have the patient after his RFA, and now we can see that we've got a black hole showing that there's no blood flow in this renal cell carcinoma.

I'm showing this clip because I think one of the things when people begin doing contrast, you can see that because we have background subtraction, we've injected the dye when the film started, there's nothing on the image now we're just finally many seconds later seeing the contrast.

One of the things, when you begin to start doing these, it becomes very anxious that you injected the dye and you don't see anything, and you really have to prevent yourself from fiddling with the knobs and turning up the mi thinking that you didn't get signal.

'Cause if you do that, you will get very poor quality enhanced ultrasounds.

This was a case of angio, excuse me, of a heman liver, which is very hard to see on B mode imaging.

But if you go back and look at this clip, you'll see that we had globular peripheral enhancement.

Now in the later phases, the lesion is becomes isod dense to the remainder of the liver, and there's no washout on delayed images.

This is another very interesting case that we think makes the case for ultrasound contrast.

This was a patient that had multiple renal masses on ct, and he had aphasic ct.

Here's the without a portal venous phase and a delayed phase.

The patient actually had a kind of renogram exam to do with 3D follow up looking for renal stones.

You can see that he had two lesions that looked cystic on both, and on all phases of the ct, the lesions looked identical.

A urologist sent the patient to us to look at with ultrasound contrast.

If you looked at the right lesion on ultrasound contrast, it actually was very enhancing and turned out to be a renal cell carcinoma.

The lesion in the left kidney had no enhancement and was actually a complicated cyst.

This very high frame rates and be able to look at a lesion at all phases of enhancement, not at just selected time points, we think is very critical in looking at lesions in the kidney as well as in the liver.

This is just to show you, even if we looked at color doppler, I think none of us would have confidence in calling this the renal cell carcinoma.

And this a benign, complicated cyst.

We find performing radio frequency ablations with ultrasound contrast in both the liver and kidney. Extremely helpful under ultrasound enhanced guidance as opposed to using CT guidance because we are able to give multiple doses of contrast.

In this case, when we're doing the RFA, you can see that after the first ablation, after we wait about five minutes for the bubbles from the RFA to resolve, you can see that we've got very good ablation of the vascularity in this portion of the tumor, but we still have marked vascularity in this portion of the tumor.

Using enhanced ultrasound in real time, we can now place RFA needle in the residual tumor and in one sitting, make sure that we completely ablate the tumor.

This is just to compare enhancement on MR to enhancement of a bosniac three lesion on ultrasound.

I think we've got basically equivalent slices here, the MR with contrast and here the ultrasound with contrast.

You can see these septations and this nodularity in this mass.

If you look at this septation, it's very, very hard to determine if there's enhancement of this septation on mr.

But if you look at the ultrasound enhanced image, you can see that not only is the septation enhancing, but there are multiple little nodularities on this septation, and this turns out to be a cystic renal cell carcinoma.

What is Needed to Perform Enhanced Ultrasound Contrast

What is needed to perform enhanced ultrasound contrast in your lab, you have to realize that you need contrast specific hardware on your ultrasound system.

This is what allows us to do the contrast images.

It's important that you don't use standard software to try to do these because the standard software uses very high mis, which bust the bubble.

You may see them on a few frames, and then you no longer see the enhancement.

You need to be able to obtain the contrast agent.

You're gonna need to start IV access.

You're gonna need two sets of hands because you're gonna need the person scanning and you're gonna need one person to inject.

How to Get Contrast Specific Software

How do you get the contrast specific software?

All major ultrasound vendors have contrast specific software.

This is all available for sale outside of the us.

The policy varies between vendors if it can be activated in the us.

More and more the vendors are willing to turn it on.

Some may turn it on without additional costs.

Some may make you purchase the license.

You need to contact your sales or application person to start this process.

I will tell you if you're in the US to be patient, but persistent because many of the sales and application persons don't understand this process.

Most of the manufacturers at a higher level will allow this to be turned on.

IRB Approval

You may need to get IRB approval.

I think you need to make the decision.

Is this gonna be a research project in which you definitely need IRB approval?

Or if this is not gonna be for research, and it just going to be for routine medical use, from an FDA standpoint, you do not need IRB approval.

Some institutions may require you to get IRB approval for off-label use as an institution in the policy.

How to Get the Ultrasound Contrast Agent

How do you get the ultrasound contrast agent?

You must use an ultrasound contrast agent that's approved for an indicated use in the United States.

Therefore you have two options, definitive latus and Opton from GE Medical.

Both of these agents are approved for the US in the use of left ventricular ejection fraction, CEUS cardiology applications.

You can contact these companies as usual.

You may actually already have these in your cardiology department or pharmacy department.

You don't even realize this, but there should be no problem in you purchasing because both of these companies will provide this drug to you even if you are a radiology department.

Contrast Specific Ultrasound Techniques

I don't have time to go through, but there are several contrast specific ultrasound techniques.

These have been worked out as the rest of the world outside the US has been doing these cases for probably 10 years.

There are different modes, and this lecture doesn't have the time to go through that.

I highly recommend that you look at the osso or woom guidelines.

There are very good discussions of these as well as references to other articles that may be very helpful.

Steps to Perform Ultrasound Contrast

There are many things you need to do to perform the ultrasound contrast.

You need to select the patient.

We've had we have a lot of referrals for this in our standard practice because our referring MDs understand this process.

We've worked with them to figure out what patients would really benefit from the use of this, informed consent from the patient.

We start an iv, we activate the drug, we perform our standard exam.

We locate the area or lesion of interest, we activate our contrast specific software.

We confirm our settings that we're using low mi.

We activate the dual screen if desired.

I think that you probably will like this option, we'll go over that in a little bit.

We inject the drug followed by the saline flush.

We start our timer, we start our clip save.

Like I said, we like to save a three minute clip.

We collect the data as needed for patients.

You may want to stay in one position.

If you're evaluating a liver lesion that you think is a hemangioma, you can stay in one position and watch that fill.

Or if you want, you can scan through the patient.

In liver lesions, sometimes it's very helpful if there is one lesion you really want to characterize.

Once you have the information to characterize that lesion in the later phases, you can scan the whole liver, look for other areas that have washout, that may locate other lesions that you are unaware of.

You can end this study and make a decision if you need to give another injection and then remove the AVI and report the case.

Let's go through these in a little bit more detail.

A lot of this information, we have a paper out in JUM that goes in a little bit more detail than I can provide in this talk, and I refer you to that for some additional information and additional references to help you get started.

Informed Consent

Informed consent.

If you're not doing research, you do not need to get an IRB informed consent.

Some institutions may require off-label use to have a formal informed consent.

We do have our patient sign a brief informed consent document.

This is not goes, does not go through our IRB.

We just give a oral and a written informed consent that says we're using a drug that's approved for cardiac use.

We're using the same dose, same power output, and the same method of injection.

We discussed this with the patient before we start.

One other thing that I would mention is that if you are gonna use opton, it does contain blood products.

We include that on our informed consent because if patients have a religious objection to using human blood products, they need to be aware of that.

IV Setup

You're gonna start the iv.

You must use at least a 20 gauge needle because we want to not bust the bubbles as we're injecting them.

We need at least a 20 gauge needle.

You may wanna consider a three-way stop c**k, one with the contrast port and one with the saline flush.

The contrast should be the one that's in line with the needle and the saline can be at 90 degrees.

Facilitate making sure that all the contrast is injected into the vein and the least amount of mechanical dis disruption.

The bubbles do not burst.

We don't want to use very high pressure when we're doing the injection, because if we do that, we can burst the bubbles.

Our use is not with the Stre way co stop c**k.

We like to use this setup.

Where we have the contrast, and we haven't talked about this in detail, but compared to MR and ct, we're injecting extremely small doses of contrast.

Our standard dose for both fin and opton is 0.3 ccs, followed by a 10 cc flush.

I refer you to the articles to get more detailed information on how to do this.

We like to do is place the needle with the contrast so that it's farther in the hub, and then the saline sticks out a little bit so that when we inject the contrast, it's farther down in the tubing, so that when we inject the saline, we push all the bubbles forward.

Activating the Agent

Both definit and opticon need to be activated to form the act of contrast agent.

If you're using definitive, you need to have what's called a vial mix.

You put this little vial in the machine and it agitates it for 45 seconds, and then it goes from a very clear fluid to a very white fluid.

This activation lasts for several hours.

You don't have to use it immediately.

We have the similar appearance with opton that it's mostly a clear fluid when it's not activated here, you can activate it just by rubbing it in your hands back and forth for several seconds.

You're going to make this so that there's no clear fluid, but white fluid.

When you take the contrast out of the vial, make sure that you try not to apply much pressure by pushing in air or taking out air, because as you make rapid pressure changes, you're gonna burst the bubbles and decrease the ability of the agent to provide ultrasound contrast.

Standard Examination

We always perform our standard examination, and we use that to identify the lesion in the area of interest.

One of the things that I think is very important, specifically if you're going to want to look at one lesion and look at the flow characteristics of that lesion throughout all the phases you wanted, when you're doing your normal exam, find a plane that the lesion stays within the field of view with the patient's breathing.

If you're looking at a hemangioma, you may want to place the probe sagittal so that you see the lesion with the patient's breathing remain within the field of view.

If you do a transverse in the patient's breathing, it may go in and out of the plane, and you only have multiple frames that you don't see the lesion.

Be aware of that when you're looking at that on your mode image, and use that to help you guide the best plane for obtaining the contrast information.

Contrast Specific Software

You're gonna activate your contrast specific software.

I can't go into this in much detail, but I refer you to the papers that I've referenced before for more detail.

Please do that before you try to get started. 'Cause this is a very important part of this study.

We like to use the dual display, which gives us a b mode image that's just basically kind of reconstructed from the low MI image.

The quality of this is not gonna be the same as you use on your standard exam, but it's more than adequate for you to identify the anatomy and find the lesion that you want to have in the field of view.

This will stay on as you do the contrast study, and it allows you to make sure you're in the appropriate position.

This is the contrast image.

Remember, people that are first starting out look at this.

It's often a black screen with just some of the areas of high reflective index that you may see present.

It's completely black, and it's supposed to be completely black.

When you inject the dye until the contrast gets to the area, which can be 30 or 45 seconds, then the screen is gonna remain black.

Especially when you get started, that it's a long period of time and you get very nervous that you did something wrong and you wanna start fiddling, you need to prevent that and do not fiddle.

The contrast will eventually get there and you'll get a good image.

Injection and Acquisition

You're gonna inject the drug, you're gonna draw up the drug.

Be careful to avoid large pressure changes.

In our practice, we use 0.3 ccs, both for finity and optisan for organs with decreased blood flow.

Or if you're gonna use a higher frequency transducer, such as if you're gonna look at a breast, you may want to use a nine linear probe, these organs that have less blood flow, or if you're using a higher frequency, you often need to double the dose to get good images.

Because we're using very small contrast, always use a one cc syringe to get an accurate measurement of the contrast.

We always follow the contrast injection with 10 ccs of saline to help get it out of the IV is also to get it into the venous system.

An extra little push to get it moving to the heart.

While one person is injecting the drug, the sonographer starts a timer and begins the clip acquisition.

Optimization

If you're going to try to optimize the system, all the major manufacturers presets are actually extremely good and it's often rare that we have to make significant changes.

You want to do that beforehand.

If you use things like ICAN or TEQ during the study, you may change the appearance of this.

If you're going to do quantitative work that we're not gonna discuss today, that will invalidate those measurements.

Be very careful.

I suspect that you probably do not need to use these additional optimization buttons once you get started.

One of the things you may wanna do too, is if you have a large patient, sometimes increasing the mi from an extremely low MI to a lower mi, staying less than 0.1, may be very helpful in getting a little bit more penetration in those patients.

If you decide to have an additional dose, that's fine.

You can give multiple doses.

The FDA approved dose is three ccs, so actually you can give 10.3 doses in the same patient.

You may want to have your doctor present to decide if you do need to have a second dose.

What we like to do is select images and send them to the PACS for review.

Overall, the contrast enhancement patterns are very similar to CT and MR, and I refer you to the reference papers for some more information.

Go to the literature and if you go to the paper we wrote in JUM, we have a nice listing of pa cases, excuse me, literature that will help you in this process.

Reporting

After you're done with the study, remove the IV and report the study.

Remember, just like in CT and mr, we need to include the number of injections, the doses, and the agent in your report.

Variations

There are many multiple variations to this standard exam that I did.

If you want to use time intensity curves for evaluation of tumor monitoring, software is available.

For example, there's Q Labs on the Philip system.

I can't go through all that information here, but if you're going to do that, please make sure you obtain that information on how to do that before you get started.

There's another technique where we can burst the bubbles and then watch a refill into the organ.

Most of the systems have a button that allow you to do this, and you'll have a short burst of very hair high mi, which destroys all the bubbles in the view, so you get a big flash of signal as the bubbles explode.

Then a black image.

Then you can watch under low mi the bubbles reentering into the field of view.

Billing and Reimbursement

Is it possible to bill for the ultrasound contrast in the hospital setting?

At this point in time, there is no reimbursement.

However, in our we do these in our private office, we actually bill using the code Q 9 9 5 7.

We actually have been getting paid by Medicare in almost all of our patients.

We only have a small number of non-Medicare insurance companies that are providing payment.

In 2001, which was the last time I checked, we were getting paid approximately $62 for our contrast fee.

When we do these cases, we've been getting almost uniform, a hundred percent reimbursement for Medicare.

There is no CPT code for contrast enhanced ultrasound yet in the abdomen in the United States, and therefore there's really no reimbursement for the additional effort that you do in performing the ultrasound with contrast.

We just bill for our standard non-contrast study.

Where to Go for Help

Where can you go for help?

Vendors, both the drug companies and the equipment companies are not allowed to assist you with off-label use.

But they are allowed to respond to specific questions when you ask, or they're able to refer you to the appropriate place to get that information.

There are training courses offered at this time in Europe, and hopefully with a possible app acceptance by the FDA of an agent in the United States.

We will have training courses in the United States shortly.

Using Ultrasound Contrast for Research

What if I want to use ultrasound contrast for research, then you will need to obtain an IRB approval.

You may want to talk to the drug companies, some of them if the research is interesting to them, may provide you with some free drug or even a monetary grant if they're interested in that study.

They can support you and give you information on how to perform the studies and work with you.

If it's you have IRB approval.

Many manufacturers are much more willing to turn on the ultrasound specific software if you're doing research and have an IRB approval for a study.

When Will Ultrasound Contrast Agents Be Approved?

I guess the elephant in the room is when will ultrasound contrast agents be approved in the United States?

We are hoping that one agent, so of you, is in the FDA process, and will be approved in the United States and in the near future.

I must say that the rest of the world has this technology.

There have been millions of cases probably at this point done with ultrasound contrast with several different agents.

This has an excellent safety record, and there are some publications out that these agents are actually probably safer than MR and CT contrast agents.

Conclusion

To conclude, this is really a brief overview, how to perform ultrasound contrast in your practice.

This was really meant for an audience in the United States, and showing them how to do off-label use.

Before you start doing patients, you really need to get a little bit more detailed understanding of the physics and a more detailed understanding of interpretation that I've given in this talk.

But hopefully in the references that I've given you, you can use as a starting point to get this information.

Contrast enhanced al ultrasound can be performed off label in the United States.

You may get reimbursement for the contrast agent as we discussed, but you will not get any reimbursement at this time for the additional time it needs to perform the examination.

I think I've shown you some cases where in our practice, enhanced ultrasound has made a big impact on the diagnosis and or outcome of our patients.

I will say, since we've been doing this, that we don't search out patients to do enhanced ultrasounds, we have referers from our referring doctors constantly, and we do these cases every week.

In fact, I think we would have a revolt if we stopped doing this because our referring clinicians actually find this to be a big help in us helping them treat their patients.

Thank you.