Contrast Enhanced Ultrasound: The Nuts and Bolts - HD

Introduction to Ultrasound Contrast

Hi, I am Richard Barr,
and today I'm gonna give you a lecture on ultrasound
contrast, the nuts and bolts.
Basically if you're going to start a program,
what are the things you need to know
and what resources do you have to help you get started?

These are the disclosures that I have.

With the recent FDA approval of Lumason
for characterization of focal liver lesions in adult
and pediatric patients, increased use of
ultrasound contrast
is expected.
The addition of ultrasound contrast
to our imaging toolbox will improve patient
diagnosis and outcomes.

Advantages of Ultrasound Contrast Over CT and MR

There are several advantages of ultrasound contrast,
over CT and MR.
These include a real-time assessment
of vascularity versus the snapshots we get with CT
and MR, the ability to subtract out background soft tissues.
So we have a contrast only image,
much improved over CT
and MR. Narrow ultrasound beam allows
for improved visualization
of vascularity in small structures such as septations
or small mural nodules.
There's no ionizing radiation,
and these are true intravascular agents
and do not extravasate
into the interstitial.
As CT and MR
so often on the delayed images will
get a different appearance.
And if you're looking to make sure
that there's no enhancement, the lack
of extravasation does improve
the ability
to say there's no contrast.
These have a short half-life approximately five minutes,
so this allows for multiple injections at one setting,
and there's no renal or hepatic toxicity.

Disadvantages of Ultrasound Contrast

The disadvantages
of ultrasound contrast over routine ultrasound is
that an IV is required.
We need two sets of hands, one for the sonographer
and one for the person injecting the contrast.
The
imaging creates a large amount of data
and you may have PACS issues,
deciding
on how
and what you need to send to PACS.
And you need additional software that needs
to be purchased for your equipment.

What Are Microbubbles?

So what are microbubbles?
Microbubbles are gas bubbles stabilized
with the lipoprotein shell
and the various agents vary in their gas content
and shell makeup. The bubbles are smaller than a red blood cell
measuring approximately 1.5 to 2.5 micrometers,
but large enough not to extravasate.
These bubbles have a non-linear response to low MI
and burst at high MI.
And as we go through the talk,
you'll understand why these are important
attributes to these agents.

Requirements to Add Ultrasound Contrast to Your Department

What is needed to add
ultrasound contrast to your department?
You need to get ultrasound specific software.
You need to purchase the contrast agent.
You need to have a mechanism to start an IV,
and you need to have two sets
of hands available for the injection.

Contrast Specific Software

What is contrast specific software?
So this is software that allows low MI techniques
to allow dynamic evaluation of all contrast phases.
Pulsing schemes include pulse inversion, power modulation,
and combinations of these two,
these sequences take advantage
of the nonlinear response of microbubbles.

So, in this slide I show you a very simple
method
of background subtraction.
So we have an alternating pulse
and we can
do that pulse either at zero degrees
or 180 degrees out of phase.
And when we do that, we get a tissue response
that's in phase, and then the exact same response
out
of phase so that when we add these together, we get
complete subtraction or almost complete subtraction
of the signal.
Whereas the microbubbles,
because they're nonlinear, do not give the same
signals that are out of phase.
So when we add them, we actually get signal.
So when we do this simple
sequence, we can see
that we will now get a contrast.
Essentially only image,
contrast agents.

Approved Ultrasound Contrast Agents

Lumason is the only ultrasound contrast agent approved
by the FDA, and it's for characterization
of focal liver lesions in adult
and pediatric patients. Definity by Lantheus
and Optison by GE Medical are FDA approved in the
United States for use in cardiology only,
but can be used as off-label
agents.

IV Access Requirements

IV access
requirements
of which healthcare professional can start an IV vary
by state and institution.
So it's very hard for me to give you
recommendations.
It has to be what you normally do.
I would recommend you look at your CT and MR department
and see who's starting IVs.
As a starting point, you always want
to use at least a 20 gauge needle
because a smaller needle
will cause the bubbles
to burst as they're injected.
The ideal way is to use a three-way stopcock
with contrast parallel to the IV
and the saline perpendicular.
So this way the
pressure on the contrast is decreased,
and you have less chance
of bursting the bubbles as they're injected.

Informed Consent

Do you need an informed consent?
And again, requirements are gonna vary
by state and institution.
As a general rule.
Informed consent should be the same as for CT
and MR for non hepatic indications,
that is you're using it off-label.
Patient should be informed the examination is off-label.
In our institution, the off-label use
is covered
by a standard
informed consent
that the patient signs
when they come to the center.
And we do not
give an additional written informed consent,
but we do give an oral informed consent saying
that it's off-label and explaining
that we're giving the same dose.
It's only that we're putting the probe in the
different location.
If the study is being done as part of a research study,
obviously IRB with an IRB informed
consent is needed.

Performing the Exams

In performing the exams, you are always gonna want
to perform the unenhanced examination.
And while you're doing that,
you wanna identify the imaging plane
where the lesion remains in the field
of view during breathing.
So this way you can then watch the enhancement
with the lesion in the field of view.
Throughout the timing of the injection, you want
to activate the drug.
Each of the drugs has a different mechanism
of activation, and we'll cover that shortly.
We want to activate our contrast specific software
and confirm that we're using a low MI technique with a MI
of less than 0.4.
We're gonna inject the drug followed by a five
to 10 cc flush of saline.
We're gonna start the timer if you want,
and then you can either save clips
or images as
your department feels
is appropriate for your setting.

So when you start the IV, again,
you must use at least a 20 gauge needle
as not to break the bubbles.
Consider using a three-way stopcock
with contrast in one and saline in the other.
The contrast should be in line with the needle
and saline 90 degrees to prevent the bubbles from going
around the bend, which may cause them to burst.
And you have to remember
that you really shouldn't use a high pressure injection
as this will burst the bubble.
So injecting the contrast agent over
approximately five
to 10 seconds is what is required.

Activating the Drug

So
you need to activate the drug
and each of the three agents have a different method
of activating the drug.
So
I'm gonna go over the Lumason since this
is the FDA approved.
It's supplied as a lyophilized vial, and it's also
provided with a five cc
saline syringe and a spike.
So you put the
spike on the
saline syringe,
and then insert the spike into the vial
and inject the five ccs.
And here you can see we've got
some foam and a clear liquid.
Then what we want to do is shake this
vigorously
for about 20 seconds
to disperse the bubbles within the contrast so
that at the end it has a milky appearance.

Dosage

The dosage
required for Lumason is 2.4 milliliters,
regardless of weight.
The recommended dosage
of Lumason in pediatric patients is 0.03 milliliters per
kilogram with a dose up to 2.4 milliliters.
A second dose can be administered.
However, the total dose should not exceed 4.8 milliliters.
For
Definity
and Optison, we usually perform the examinations
with a 0.3 milliliter
injection.

Saving Images

You wanna save images,
and again, for liver scanning
you should be
performed for at least three minutes.
And in some cases, hepatocellular carcinomas may not show
washout until five minutes.
So you may, in certain cases even want to lengthen the time
that you are
collecting data.
You can save the entire clip, which
creates
PACS issues, or you can come up with a
institutional
way where you either take selected images
or
save short clips
from the long clip
to send to the PACS.

Interpretation of Ultrasound Contrast Exams

In this shorter period of time,
I really can't go over interpretation well.
So I'm briefly gonna highlight interpretation of a couple
of the major indications.
But again, when you're starting your lab, you do need
to get some hands-on experience
and
more extensive training in
how to interpret the images.

In general, the interpretation
and the enhancement is gonna be very similar to CT and MR.
So for the liver
ultrasound contrast wash out is indicative
of a malignant lesion.
Globular peripheral enhancement is diagnostic
of a hemangioma
and focal nodular hyperplasia
as a spoke wheel arterial appearance
with rapid intense filling and eventually becomes isodense.

And in this table I've tried to demonstrate
the different enhancement patterns for different diseases.

Liver Lesion Examples

So
here is our without contrast image.
You can see a hemangioma is gonna be
hyperechoic compared to the background.
And then we see globular enhancement, which fades with time,
as well as filling in the lesion so
that it becomes almost isodense or probably isodense.
In the delayed phases, FNH,
we get the spoke wheel appearance,
often having a central scar on the delayed images
that shows no enhancement
and for most of the time, again,
becoming isodense.
In
the late phases
adenomas have a vascular pattern
where we see vessels coming in from the outside
and again
decrease in enhancement
and eventually becoming isoechoic to liver,
although there can be some variability.

Below this red line,
you can see all the metastatic lesions,
and you can see that for all of these,
that the characteristic is wash out on delayed images.
So the lesion is
less
contrast than in the background liver.

When we look at HCCs, the washout tends
to be relatively slow,
and like I said, can extend up to five minutes,
but if you notice the washout in cholangiocarcinomas,
the washout is much faster.
And then in metastasis
the hypervascular metastasis tend
to wash out very
rapidly.
And the hypovascular masses may not enhance
as much initially, but again, show relatively rapid washout.

Literature on Ultrasound Contrast for Liver Lesions

If we look in the literature
on
ultrasound contrast for liver, for characterization
of focal liver lesion,
ultrasound contrast has its sensitivity of 97%
and the specificity of 91% for focal liver lesions,
diagnostic accuracy increases from 35 to 42%
for non enhanced ultrasound to 87 to 88%
with contrast ultrasound.

In this table, I've taken three large meta-analyses
and
presented their data.
You can see that the sensitivity is about 90%
in these two studies.
And our specificity again
is in the eighties
to nineties percent.

In this study in the middle by Neuhaus,
he only looked at lesions
that were less than two centimeters,
and you can see that there is some decrease in
sensitivity with the smaller lesion,
but the specificity is about the same.

There were several prospective studies that looked at
focal liver lesions
and again, sensitivities in the order of 90 to 95%,
and specificities again, around 90 to 95%.

If we look at studies that compared ultrasound contrast
with plain ultrasound
you can see that again,
increased sensitivity with the contrast from the low fifties
to the low eighties in this study,
and from the
high forties
to the
low nineties in this study.
And the specificity
also increases markedly
from forties to 95% in this study
and from the twenties to about 80%.
In this second study, if we look at studies
that compared
enhanced ultrasound compared
to enhanced CT
there are three studies.

This study actually
only looked at indeterminate masses on CT.
So I'm only gonna give you the sensitivity
for the ultrasound contrast and CT,
but again, this was a selected group
and this is why the CT values are so low.

If we look at the studies that compare them directly,
you can see that
in both studies there was increased sensitivity
of ultrasound contrast over contrast enhanced CT, as well
as a slight increase in specificity in one study,
and a significant increase in
in a second study.

If we look at studies that directly compared ultrasound
contrast
with contrast enhanced MR.
There are three studies,
and again, you can see that the
sensitivities
in two of the studies are better
in ultrasound contrast than contrast enhanced MR.
And are basically equivalent in the third study.
And the
specificities
again,
in these two studies are
improved with ultrasound
contrast over contrast enhanced MR.
And similar in the third study

The conclusion of the meta-analysis
by Strobel
which again had over 7,000 patients showed no significant
difference in specificity, 88% versus 83%
with the P value of 0.1 between ultrasound contrast
and contrast enhanced CT and MR.
Sensitivity was significantly better
with ultrasound contrast
and CT and MR at 95% versus 89% with a p value
of 0.3.

If we look at the sensitivity for individual
entities
from this meta-analysis, the sensitivities
for diagnosing hemangioma, focal nodular hyperplasia,
hepatocellular carcinoma
and metastasis was very similar at about
high eighties
and low 90%.

Examples of Liver Lesions

This is just an example of a hemangioma.
Here you can see in the early phases, we start
to see some peripheral globular enhancement, which fills in
with time and becomes isodense on delayed images
with focal nodular hyperplasia.
Here you can see the lesion is relatively
isoechoic.
On the B mode images, when we inject, we can see a scar
centrally here, and a spoke wheel appearance on the arterial
phase, the lesion becomes markedly
enhanced compared to the normal liver.
And then, and the delayed images becomes relatively
iso intense
to the normal liver.

An example of a hepatocellular carcinoma,
relatively large heterogeneous lesion
with some areas without enhancement,
most likely representing necrosis
in this early arterial phase.
And you can see that there's marked washout on,
on the delayed images.

Interpretation of Renal Lesions

Moving on to interpretation of renals.
One key difference between contrast enhanced CT
and contrast and MR, is
that the ultrasound contrast agents are not
excreted into the urine.
So here you're not going to get enhancement
of the collecting system.

For benign cystic lesions
including Bosniaks
one through three, we do not have any enhancement.
If we have malignant cystic lesions, we'll have enhancement
to the cyst wall septations or the nodules.
And RCC in general has rapid enhancement
with washout on delayed images.

Again, here's a similar table
where we have the gray scale images arterial
nephrographic and the excretory phase
for the kidneys.
And you can see that a benign cyst shows no enhancement.
A benign, complicated cyst, regardless of the Bosniak score,
shows no enhancement of the
internal septations or the cyst wall.
A malignant complicated cyst
no matter
what the Bosniak score is, will show enhancement
of the septations and nodular densities.

Renal cell carcinomas
will show marked enhancement,
usually more than the liver
with washout on the
delayed images.
And if there is necrosis, there'll be a central area
that shows no enhancement on all images.

An echogenic RCC tends to have marked
enhancement greater than the normal
kidney very early in the arterial phase.
And then shows washout.
A angiomyolipoma in our experience tends to have
less enhancement.
Usually a little bit less than the normal renal cortex,
often with a peripheral enhancement.
And then shows washout
on the delayed images.

Literature on Ultrasound Contrast for Renal Lesions

If we look at the literature
ultrasound contrast has a sensitivity of a hundred percent
and a specificity of 90%, a positive predictive value
of 95%,
and a negative predictive value
of a hundred percent in characterizing
indeterminate renal masses
in a
study
that
actually looked at
over a thousand cases.

Examples of Renal Lesions

So here's some examples of things that
we can compare.
So if we have a Bosniak
two,
two F
or three complicated cyst where we've got
nodularity
or septations within the cyst,
a benign lesion will just show no enhancement.
A malignant lesion will show
enhancement
of the nodular components.
And I also want to point out again,
that the renal cortex is gonna enhance
more than the medulla.
And again, since we do not have excretion of contrast,
we can usually identify the medulla from the cortex in all
phases because it enhances less than the cortex.
And again, no enhancement at all
within the collecting systems.

Again, comparing
two echogenic masses in angiomyolipoma
and a echogenic renal cell carcinoma.
In our experience, we tend to see marked enhancement
of the echogenic renal cell carcinoma in the first few
seconds in the arterial phase
that is more than the normal cortex,
and then
washes out with time.
With the angiomyolipoma, we often see enhancement
that's not greater than the normal cortex,
and often has a peripheral distribution
and then does show
washout in the later phases.

And we always, when we think something is an
angiomyolipoma, get another test to demonstrate
that there's macroscopic fat in the lesion.

This is
the table of
classification
that we presented in our paper in Radiology.
And basically
if there is no flow within a lesion,
it's benign.
If the
lesion is equal to normal cortex in all
phases of enhancement,
and you often see a central
medullary pyramid.
This is a benign lesion.
It's a pseudotumor
echogenic masses with enhancement,
again, less than the cortex
with often a peripheral distribution,
we believe is an angiomyolipoma, but always get an MR
or CT to confirm
that there's macroscopic fat in the lesion.
Constant flow of bubbles
with a fine septation without nodularity is an
indeterminate
lesion
when we did this study.
But we have followed these patients for up to 10 years,
and they've all been benign.
So we believe you, if you see bubbles going
through a septation or you have a very fine
enhancement
of the septation without nodularity,
that's a benign finding.
And basically anything that shows enhancement
is most likely a malignant lesion.
I've not included in this
the infectious causes
pyelonephritis because that will show enhancement,
but those are usually not sent to us
because they're diagnosed clinically.

Clinical Examples for Renal Lesions

So just some clinical examples.
This is a case to show you the
a patient
with renal failure that had a CT scan
of this kidney,
cannot get contrast.
We can use ultrasound contrast here
to define this echogenic renal cell carcinoma with an area
of an
necrosis centrally.
And again, here you can see the medullary pyramids are not
enhancing as much as the normal cortex.

Another interesting case demonstrating the real-time
capabilities of ultrasound versus the snapshot
pictures in CT.
Here is
images
of a patient that happened
to have two lesions in the upper pole of the kidney
for a renal stone protocol.
So we have without portal venous and delayed images.
And you can see the lesions on CT are identical in all
three phases, but if we look at the ultrasound images in the
early arterial phase
the lesion in the right kidney is markedly enhancing
and was a renal cell carcinoma.
The lesion in the left kidney shows no enhancement
and was a benign cyst.

Again, to show you the advantage of ultrasound contrast
with its thin
slice thickness, here's an MR
with contrast of a Bosniak III cyst.
And again, you can see this solid
component in the septations.
The question is, is there enhancement of these
lesions
or not?
But you can see on the MR I'm sorry, in the ultrasound
with contrast, we can see
that this lesion shows no enhancement whatsoever
and the
septations enhanced,
so we can actually see little nodules hanging off them in
the cystic renal cell carcinoma.

Another example of a pre and post contrast MR.
You can see these septations better on the post
contrast MR, but how confident are you
that this is really enhancement where in the ultrasound
with contrast
you can clearly see
that there's marked enhancement in nodularity
of these septations.

This was an interesting case of a patient
that had a 20-year-old renal transplant.
My partner was doing an angioplasty
for renal artery stenosis
and saw a blush in the kidney when he was doing the exam.
The patient had a contrast enhanced MR
and a contrast enhanced CT that were normal.
We did an ultrasound contrast,
and here you can see a markedly enhancing
renal cell carcinoma
that we biopsied under ultrasound guidance.
This lesion only enhanced for
four or five seconds.
So we picked it up on the ultrasound contrast,
but the timing was off on CT
and MR, which is why the lesion was missed.

Other Applications of Ultrasound Contrast

And then to show you another
excellent application of ultrasound contrast,
we ablated the kidney,
and here you can see there's no flow left
within the
renal cell carcinoma.

Other interesting things we can look for. Endoleaks.
Here is actually a type one, sorry, that's a typo
endoleak where we can see that there's a one centimeter gap
between the stent
and the native aorta.
And we have contrast extending out.
This was a patient with renal failure
and was being followed with CT without contrast
for
years.
And the leak was not even noticed
because there was no change in the native aorta size.

Another example of
trauma.
You can see
some enhancement here.
And again, some
questionable increased density.
Is there some enhancement of this lesion
or residual enhancement,
or is this excretion by the
collecting system?
And here you can see that on the ultrasound contrast,
there's absolutely no enhancement.
And this was excretion into the collecting system
and there's
no enhancement in what turned out
to be a hematoma.
Again, ablation is a very good application for this
lesion.
Here you can see on CT
again,
it was done without contrast,
but you can imagine with contrast,
it would be very difficult
to determine if this ablated area showed any enhancement.
But the excellent background subtraction
with ultrasound contrast, that allows us to clearly see
that there is no enhancement left in the ablated
renal cell carcinoma.

And when we're doing these ablations, we can do a
contrast injection at that setting.
And here we can see we have ablated this area of the tumor,
but we still have some area of enhancement left
and now we can reposition at the same setting
and ablate this additional tumor.

Cost Comparison

If we look at the cost
of ultrasound contrast versus the cost of CT and MR.
There was a
recent study done in Europe
that looked at 157 patients
that had 160 focal lesions.
And what they found out that the cost per procedure
for an ultrasound
enhanced scan was 85 euros versus 155 for CT
and 174 for MRI.

Guidelines and Training

There are several published guidelines for both hepatic
and non hepatic uses by Hamm
and the European Federation Societies
of Ultrasound and Medicine and Biology.
And I highly recommend you look at these
if you're gonna start a program.

With the recent FDA approval, the development
of training courses are being developed.
You can contact your Bracco
Diagnostic
representative
or your ultrasound vendor to
find out if there are available courses.
And there are available courses in Europe
and courses are being developed in the United States,
and I suspect within the next year there'll be some hands-on
courses within the United States.

Notifying Referring Doctors

I think it's important that you
notify your referring doctors when you
do this to let them know.
Since this has not been widely available in the
United States, they're probably unaware
and I think it's important
that you notify your referring doctors of the advantages
of ultrasound contrast.

Contraindications and Adverse Events

There are some contraindications
to ultrasound contrast, known
or suspected right to left bidirectional
or transient right to left cardiac shunts.
Although actually
this week, the FDA
has approved the use
in this patient with Optison.
And I suspect the other drugs will
come shortly.
And the history of sensitivity to the agent
or any of its
inactive ingredients.

Adverse events
mostly headache and nausea.
These are usually mild and transient.
The adverse rate has been reported at 0.13%
with serious adverse events
in less than
one per
10,000.
The adverse events typically occur within 30 minutes
of administration.
The risk of serious reactions may increase in patients
with unstable cardiopulmonary conditions.
As for all facilities administering contrast agents,
cardiopulmonary resuscitation personnel
and equipment should be readily available.

Billing for Ultrasound Contrast

For billing, there is currently no CPT code
for ultrasound contrast.
You can bill for the non enhanced exam.
For Lumason only, you can use the administration
of contrast code 96374
and again for Lumason only, you can bill with
Q9950
for the cost of the agent.

And in this table that
I can make available
lists
for the office outpatient
hospital
and inpatient hospital codes that can be used.

Conclusion

So to conclude, ultrasound contrast is a safe examination
without ionizing radiation that can be used in cases
of renal impairment and obstruction
and used in patients with contraindications for enhanced CT
or MRI, real-time vascular assessment in narrow slice
thickness or advantages of CT over
ultrasound contrast over CT and MR.
Contrast ultrasound contrast can help characterize focal
liver lesions and indeterminate renal lesions
with accuracy similar or greater than CT and MR
and ultrasound contrast is really now an important addition
to our imaging toolbox.
Thank you.