Contrast Enhanced Ultrasound in Pediatrics - HD

Introduction

Hello, my name is Beth McCarville.

I'm a pediatric radiologist at St. Jude Children's Research Hospital in Memphis, Tennessee.

And today I'm going to be talking about contrast enhanced ultrasound in pediatrics.

The objectives of today's talk include a discussion of the properties, benefits and limitations of contrast enhanced ultrasound, and especially as they apply to the pediatric population.

I will also discuss the history of contrast enhanced ultrasound safety considerations and the safety data that is currently available for adult and pediatric patients.

And finally, I will discuss the current status of pediatric contrast enhanced ultrasound in the United States.

Benefits and Limitations of Contrast Enhanced Ultrasound in Pediatrics

The benefits of contrast enhanced ultrasound, especially in children, are that it's a non-ionizing modality, and this is especially important in our pediatric population.

Also, no sedation is required to perform ultrasound, as is often necessary for MR examinations and sometimes even for CT.

Small patients in general are excellent candidates for ultrasound and therefore also ideal candidates for the application of contrast agents in ultrasound to optimize ultrasound imaging.

This modality is portable.

It's lower cost than our other cross-sectional modalities, and there's also no associated nephrotoxicity with this contrast agent as opposed to our iodinated contrast agents.

In fact, this agent can be given to patients with renal insufficiency, which is a benefit of this agent over both iodinated and gadolinium contrast agents.

Limitations with ultrasound in general is that it is very operator dependent and not all lesions are amenable to ultrasound visualization.

Another benefit for me is that at our institution, I'm using ultrasound contrast agents as a surrogate marker of tumor blood flow, and I'm able to quantitate contrast agent flow into tumors and assess their response to anti-angiogenic therapies.

Properties of Ultrasound Contrast Agents

This is a photo micrograph of ultrasound contrast agent taken in a Petri dish with red blood cells.

So this is the contrast agent here, and you can see that it is variable in size, but the larger spheres approximate the size of a red blood cell, and this is beneficial when you're imaging tumor blood flow.

So ultrasound contrast agents with MR and CT contrast agents, these are much larger particles and our MR and CT contrast agents are very small particles, and because they're larger, they remain in the vascular space.

The ultrasound and CT contrast agents diffuse freely from the intravascular space into the interstitial tissue.

So if you're trying to quantify tumor blood flow, it's much more straightforward with an agent that remains in the vascular space.

These agents are also very highly reflective and can be given in very small doses, much smaller than is commonly used for iodinated and gadolinium based contrast agents.

And because they are highly reflective, we are able to visualize them down to a capillary level.

Safety Considerations

I want to spend some time discussing the safety considerations associated with these contrast agents because I think that this has been one of the barriers to their wide spread use in our country.

These contrast agents have been approved for adult use in over 50 countries worldwide.

Currently in the United States, they are FDA approved only for use in adult cardiology patients.

However, there have been over 3 million diagnostic injections of these contrast agents given worldwide, and they have been shown to have an excellent safety record.

When we're considering adverse reactions that occur with our imaging contrast agents, the most serious adverse reaction that we encounter is anaphylactoid reactions.

And if we look at the incidents of anaphylactic reactions in patients receiving ultrasound contrast agents, it's very low at one per 7,000 applications for a rate of about 0.014%.

And this is much lower than the rate of anaphylactoid reactions that we see with iodinated contrast agents.

Despite this, in 2007, the FDA issued a black box warning for these contrast agents, which was subsequently revised in 2008.

And I want to spend a little time talking about these black box warnings and where we stand today.

2007 FDA Black Box Warning

In 2007, the first black box warning was issued in response to four deaths and about 190 serious cardiopulmonary reactions that were temporally related to the administration of ultrasound contrast agent, but not clearly causally related to these agents.

And these were all in adult cardiology patients.

Based on these events, the FDA issued this warning that all patients should be assessed for the presence of underlying conditions that precluded the use of these contrast agents.

And I'll show you the list of contraindications, which was fairly lengthy.

They also recommended that all patients be monitored for 30 minutes following the administration of one of these contrast agents.

This is the list of contraindications that was used at the time of the initial black box warning.

As you can see, it's fairly lengthy.

Most of these are cardiac or pulmonary conditions that would preclude the patient from receiving the contrast agent.

So this affected the population of patients that was primarily receiving these agents who were cardiology patients.

So the adult cardiology community, the use of these ultrasound contrast agents then plummeted after the black box warning.

And the adult cardiology community undertook numerous very large retrospective studies to investigate whether or not these contrast agents really increased the morbidity and mortality of adult cardiology patients.

This is taken from a nice review article that was done by Michael Main that summarizes the largest of these retrospective studies.

This included over 200,000 patients, and in most instances, there was no increase in morbidity or mortality associated with the use of these contrast agents.

And in a few cases there were a few non-fatal serious reactions, but a very low rate of serious reactions.

2008 FDA Revision

So based on these findings, the FDA revised the black box warning in 2008, and they reduced the number of contraindications and they removed the recommendation for the 30 minute monitoring after administration of these agents.

So the current list of contraindications for ultrasound contrast agents are shown here.

The one cardiac contraindication that remains is right to left bidirectional or transient right to left cardiac shunts.

And any hypersensitivity to the contrast agent, or in the case of Optison to blood or blood products, is also a contraindication.

So there has been some question as to the necessity to have a right to left shunt as a contraindication for the use of these agents.

This recommendation is based on very limited rodent data that was obtained when there was speculation about micro embolic events related to administration of macro aggregated albumin microspheres that are used for nuclear imaging.

And it's interesting that there is no such contraindication for the use of these radioactive macro aggregated albumin microspheres in nuclear imaging, but that the contraindication remains for the use of ultrasound contrast agents.

So there's been a push recently to have this right to left shunt contraindication removed from the package label.

Pediatric Safety Data

So there is an abundance of literature regarding the safety of ultrasound contrast agents in adults, but there's very much less literature available for their safety in children.

So at our institution, we performed a retrospective review of the safety profile of ultrasound contrast agents in our pediatric population, pediatric oncology population.

So our study included 34 subjects who had a median age of 8.7 years, but range from less than one year up to about 21 years of age.

These patients underwent a total of 134 contrast ultrasound examinations.

The vast majority of the examinations were performed with Optison, but some were performed with Definity.

Most of these patients did receive a dose of 0.5 ml of both agents.

So at the time that we were performing these studies, the black box warning was in effect.

And so our own institutional contraindications for the use of contrast ultrasound mirrored those on the black box warning.

So we required all of our patients to undergo a 12 lead EKG and echocardiography to exclude right to left shunting and any underlying cardiac abnormality within 90 days before undergoing contrast ultrasound.

We also required all of our patients to have a physical examination and complete history to exclude the possibility of any past cardiac surgery or any other cardiac abnormality.

And we did perform screening ultrasounds on all of these patients to make sure that we were able to visualize the target lesion of interest on non-contrast ultrasound before administering a contrast agent.

In addition to our screening, we monitored all of our patients for 30 minutes after each injection.

We monitored their heart rate, the cardiac rhythm, and their oxygen saturation.

We also performed parent and subject interviews immediately before the injections and then again immediately after the injections to determine if any subjects experienced any reaction.

So our patients had a wide variety of underlying solid malignancies, and about 40 of our examinations were performed prior to the initiation of chemotherapy.

And 94 were performed while patients were undergoing chemotherapy.

So these were patients that were not otherwise healthy.

All of these patients had some underlying illness either due to their primary malignancy or to the toxic effects of chemotherapy.

Even in this patient population, we saw no clinically significant change in any of the cardiac or pulmonary parameters that we monitored.

Were there three mild and transient adverse reactions reported.

All of them occurred with Optison.

Two were altered taste and one was a mild tinnitus, sore lightheadedness.

Interestingly, none of these reactions occurred when these patients underwent repeat injections on follow-up examinations.

We also did not witness any event that we could attribute to the contrast agent in our very young subjects who were unable to verbalize whether or not they were having an adverse reaction.

Current Institutional Practices

Currently at our institution, we continue to require 12 lead EKGs and echocardiography, but only for our research subjects.

And this is because there's no direct clinical benefit from undergoing these research contrast ultrasound examinations to these patients.

And therefore, we set the bar a little bit higher for these safety requirements.

We have since we reported the safety data.

We have added Optison to our institutional formulary for clinical use.

And when we use it in a clinical setting, we do not require those patients to sign consent because we don't require consent for any of our other contrast agents that we use daily.

We have purchased new contrast specific software since we perform these studies.

And this has allowed us to lower our dose to 0.3 ml for all patients.

We no longer monitor any of our patients, our research patients, or our clinical patients after performing our injections.

We do continue to have a radiologist present in the room for all injections, but this isn't really for safety reasons.

This is more just as a quality assurance to ensure that injections are performed correctly and CEUS clips are recorded correctly.

Broader Pediatric Literature

So our data adds to the limited pediatric literature that is available.

This is probably the largest study that's been done to look at the safety of contrast agents in children was from this very large European survey that was conducted in 2012.

And in this survey there were 948 reports of IV applications of SonoVue, which is the only contrast agent that's available in Europe.

In this study, the mean age of patients was five years, but it ranged from zero to 18 years.

And the main indications were for trauma and oncology.

There were no serious adverse reactions reported.

There were six minor adverse reactions.

Again, altered taste was the most common, followed by rash and one hyperventilation.

So from these studies, we can conclude that the IV application of ultrasound contrast agents in children is safe and is well tolerated.

And this opens the door for others to start using these contrast agents in children for other indications.

And hopefully this will allow us to reduce the need for CT and MR and avoid exposure to radiation and sedation.

Current Status of Contrast Enhanced Ultrasound in the United States

I want to talk now about the current status of contrast ultrasound in children in the United States.

Contrast ultrasound in pediatrics has been ongoing for about 15 years already in Europe.

So we're really pretty far behind here in the United States.

Before 2011, there was only one center, and that was St. Jude that was performing any contrast ultrasound in children.

And it's very hard to make progress when you're the only institution that is performing these studies.

In 2011, the Society for Pediatric Radiology formed a contrast enhanced ultrasound task force.

And since that time, we've been able to make substantial progress.

In 2012, the SPR was invited to join the International Contrast Ultrasound Society.

We now have an official SPR Liaison on the ICUS board of directors.

Casa D is our pediatric director on the ICUS board of Directors, and this allows us to participate in their annual meeting.

We can give educational presentations at their annual meeting, and it also gives us a voice on the board for policies and recommendations and guidelines that come from this important professional organization.

So there are now several institutions throughout the United States that are using ultrasound contrast agents off-label for clinical indications.

These include the University of Michigan, Boston Children's Hospital, St. Jude in Memphis, CHOP in Philadelphia, Lucille Packard at Stanford and Children's National Medical Center.

And these sites are using the contrast agent for clinical indications for assessing liver lesions, trauma and bowel inflammation, and also for intravesical use for contrast enhanced voiding urography.

Clinical Example: Liver Lesions

I'm just going to show one example where we found contrast ultrasound to be extremely useful clinically.

Liver lesions develop commonly in children after treatment for cancer therapy.

We find liver lesions not uncommonly on surveillance imaging that we're performing in these children once they've finished therapy.

And this is an example of such a case.

This was a 13-year-old boy who was previously treated for stage four neuroblastoma.

He underwent a CT examination when he developed a small bowel obstruction.

And on the CT that was obtained, this enhancing liver lesion was found as an incidental finding.

So we performed contrast enhanced ultrasound in this patient, and we were able to demonstrate the typical features of focal nodular hyperplasia.

On contrast ultrasound during the earlier arterial phase, we saw a nice spoke wheel central feeding vessels, followed by centrifugal or central to peripheral enhancement of the lesion.

Also in the arterial phase on the portal venous phase, the lesion had this light bulb appearance and then on a delayed phase with iso enhancing with surrounding normal liver.

So these are all features that are typical of focal nodular hyperplasia.

This allows us to confidently diagnose what these liver lesions are and avoids needing to follow these patients with repeated CT and MRs to try to confirm that these lesions are not metastatic deposits.

Ongoing Research Studies

So there are several sites also in the United States who are undertaking prospective research studies in children.

And these sites have obtained INDs from the FDA to perform these research studies.

These include University of Michigan, where they're looking at the value of contrast ultrasound in inflammatory bowel disease, Boston Children's Hospital, where they're looking at the value in trauma.

We continue to use contrast ultrasound in our pediatric oncology population at St. Jude and at CHOP, they have gotten approval to use contrast ultrasound for the assessment of juvenile idiopathic arthritis and for contrast void ultrasonography.

And they have INDs pending for the use of bowel disease and in trauma.

Educational Activities

So there are also a growing number of educational activities that are available to interested parties.

The first dedicated pediatric contrast ultrasound sessions were given at the ICUS meeting in 2013, and also in 2013 at the American Institute of Ultrasound in Medicine annual meeting this year.

We also again had a focused pediatric session at the AIUM meeting and contrast ultrasound was discussed at the ultrasound protocol session at the Society for Pediatric Radiology meeting.

We again have planned courses for pediatric contrast ultrasound that will be given at the SPR meeting and at the AIUM meetings in 2015.

Last year was the first year that this international pediatric contrast enhanced ultrasound course was offered at King's College Hospital in London.

This was a very successful course.

It consisted of a morning of didactic lectures followed by an afternoon of live cases.

It got a very enthusiastic reception and is going to be repeated in June of 2015 and has been expanded to a two day course.

So the SPR task force has developed a website that is available to SPR members where you can go and get all kinds of information about pediatric contrast ultrasound including all of the current publications on this topic in children.

We have various cases available for review on this website, various different pathologies, and we've also asked the vendors to become involved in our website.

Most of the vendors, if not all of the vendors now have contrast specific software packages that are available for purchase with their equipment to be used on their equipment.

And we've approached the vendors and asked them to share the technical information about what they do have available for contrast ultrasound on their equipment for the SPR membership as a reference.

Future Directions

So we are making a lot of progress just within the past three years.

We've had some major accomplishments in education, and the use of contrast ultrasound is continually expanding in the United States.

We will continue our educational activities.

We will promote contrast ultrasound in children, and there are other applications that are currently being investigated, including testicular torsion, contrast ultrasound and the assessment of blood flow in the pediatric hip and contrast ultrasound and ischemic and hypoxic brain injury in children.

And this is a very exciting time for this modality in children, and I'm sure that it will continue to grow in the future.

Thank you for your attention.