Safety of Ultrasound Contrast Studies - SD

Introduction

Hi, I'm Sharon Mulvey.

I'm a cardiologist at Mayo Clinic in Rochester, Minnesota,
where I'm also a professor of medicine
and consultant in cardiovascular diseases.

I have been involved in contrast echo research since the
early 1990s,
and have the opportunity of spending about 40%
of my time in the Echo Lab
and about 20% of my time doing research relevant
to contrast work.

And I look forward to sharing with you my lectures now.

Safety of Ultrasound Contrast Studies

Hi, I'm gonna be discussing my lecture on safety
of ultrasound contrast studies.

I do have research grants with Latus Medical Imaging
and Astellas Pharma, and I will be discussing the off-label
use of di definity and OPTON safety
from the definition of the International Organization
for Standardization, for medical device application
of risk management to medical devices ISO 1 4 9 7 1.

The definition is freedom from unacceptable risk.

The intent of this lecture is to put the safety of
the contrast agents that we use in the context
of their clinical applications.

Ultrasound Contrast Agents

Ultrasound contrast agents are microbubbles,
which are in the order of two to eight microns, maximal,
with most of the clinically what used ones
that we use approximately two microns.

They are generally enclosed by lipid shell
or albumin surfactant, galactose or polymer.

And within the microbubbles are gases,
most commonly per floral carbon gas.

Ultrasound contrast agents are pure intravascular tracers,
which are non-toxic and inert
and small enough to pass through the pulmonary vasculature,
and they're persistent enough to reach the left ventricle
and or the myocardium.

Clinical Example

The use of contrast agents is demonstrated in this
particular patient case representation.

This is a 48-year-old male with a body mass index of 51.

As you can see, it is very difficult
to interpret the left ventricular function in this patient.

We see that the LV is on the left side of the image here,
and there is absolutely no endocardium visualized.

We can see an epicardial layer.

This is clearly a patient that fits the criteria
for the application of contrast agents being greater than
or equal to two contiguous segments
not seen in any one view.

The risk of having
suboptimal images is the reduction in diagnostic confidence, an increase in inter observer variability,
and a need for additional downstream testing.

And worse is a misdiagnosis
or a missed diagnosis in this patient.

As you can see, the addition of contrast
to the imaging protocol clearly outlines
the endocardial border.

With this being the infra lateral wall
and the angio septal wall, the apex clearly visualized.

We have a papillary muscle here.

The left ventricular opacification is excellent.

The endocardial border visualization is complete,
and we can see that the patient clearly has
hyperdynamic systolic function.

Impact of Contrast

The impact of contrast has been nicely quantified in a
paper from the Baylor group with the first author Kurt,
and indeed in the patients
where we frequently have the most difficulty.

This is in the sicu, the Surgical Intensive Care Unit,
the medical Intensive Care Unit, where
uninterpretable studies are very frequent.

Technically difficult studies are often seen as well.

With contrast, we can convert these uninterpretable
or technically difficult studies into adequate
studies of good quality.

In addition, not shown on this particular slide,
but this group also documented
that there is a significant clinical impact on the decision
making with respect to medications
and subsequent procedures that the patients
were exposed to relevant to the contrast studies.

Appropriateness Criteria

With this and much other information, the major medical
societies have published the appropriateness
criteria for transthoracic
and transesophageal echocardiography.

And very interestingly in this document is stated, the use
of contrast is indicated
and will be performed when more than two contiguous segments
of the left ventricular endocardial border
are not visualized.

This is taken from the consensus document
of the American Society of Echocardiography,
which was initially published in 2000,
and then updated more recently in 2008.

And I would refer you to this document for detailed information on the use of contrast agents.

Historical Events and FDA Black Box Warning

So with that context of contrast agent utilization in mind,
we need to review the recent historical events.

On October 12th, 2007,
the FDA introduced a black box warning based on information
that had been obtained from a post-marketing survey,
which suggested the temporal relationship,
but not a clearly causal relationship
in the exposure of patients to definity and death.

Four patient deaths were reported in a total estimated
administered number of doses of definitive
to be greater than 2 million.

In addition,
there were 190 serious cardiopulmonary reactions,
which were also of concern.

Thus, the black box warning
was a class warning, which precluded the use
of the class of perf lutrin containing ultrasound contrast
agents in the following patients, those with worsening
or clinically unstable congestive heart failure, acute mi
or acute coronary syndrome, serious ventricular arrhythmias,
respiratory failures, severe emphysema, pulmonary emboli,
or other conditions that could be
causing pulmonary hypertension.

These were new warnings
and contraindications added to the preexisting
labeling, which had stated only right to left bidirectional
or transient right to left cardiac shunts hypersensitivity
to perf florin and intraarterial injection as a
not advised and contraindicated mode of delivery.

In addition, the most onerous addition of the black box warning was that all patients, not just the ones
with concerns with their cardiopulmonary status,
but in all patients, we were to have a 30 minute period
of observation documenting vital signs, ECG,
and O2 SAT monitoring.

Well, this was a very onerous requirement,
and indeed the use of contrast plummeted.

There was a overwhelming response on an international
and global basis from the physician community,
and the response was very active and very proactive
because of the recognition of the usefulness
of contrast agents in just the patients that the FDA was now
contraindicating their use.

Thus, new contrast agents safety data was published.

We had this data, many of us,
but had not focused on presenting it in the scientific literature
as there was not a recognized need.

Also, a special meeting of the DA cardiorenal panel,
which was devoted to contrast agent safety was convened in
June, 2008 to hear presentations
regarding the concern of the black box labeling.

In the interest of time, I'm not going
to go into every single contrast echocardiography safety
study that was published in the intervening several years, but a plethora were,
and these are very nicely summarized in this recent paper
from our group looking at the safety
of contrast agent use during stress echo,
where we looked at 26,000 patients that had accumulated in our stress echo database.

And 10,000 of these patients had received contrast.

And we queried the follow up
of these patients in both the immediate
and the long-term periods,
and found that the use of contrast agents
during stress echo was not associated
with an increased short-term or long-term risk of death
or mi.

And within this paper, I would refer you
to table five, which does nicely summarize the other studies and published reports
that had been done in the intervening time.

And there are several more beyond as well, that have subsequently been published.

But the importance is that
when looking at death less than 24 hours adverse events
within 30 minutes, or death less than 24 hours death,
less than 24 hours
or long-term death, there was no
increase in the patients
that had received contrast versus those that had not.

And this summarize, these studies
summarize almost a quarter
of a million cardiac patients across the world,
which have carefully documented data in which
it has shown that they have received contrast, echo contrast
during an echocardiogram without evidence of increased death
or serious cardiac event.

The allergic rate is approximately one in 10,000 where
anaphylactoid type reactions have been recognized,
and I'll speak to that subsequently.

Putting this into context, the comparative mortality
of cardiac procedures contrast echo, even if it was
that there was a mortality of rate of one in half a million
and previously reported in the European experience.

Concerns regarding So nvu are noted here.

When we look to compare other investigative measures
that we use routinely in cardiology,
the mortality rates are significantly higher,
and this is certainly well in line with a rate
that can be acceptable given the information
that we receive from the technique.

Key Safety Study

This is a very interesting study that I would like
to highlight in that context.

And this is from Mike Maine
and his group where they looked at the acute mortality in
hospitalized patients undergoing echo with
and without contrast,
it was a multicenter study interrogating the premier
database in over 4.3 million patients.

And if we look, these 4.3 million
patients were divided into those
that had not received contrast,
and those that did,
there were 58,000 definitive enhanced echocardiograms
that were in this total population.

And this is interesting to note that when we look at
the conditions that these patients had,
they were already very sick patients,
much more sick in the definitive enhanced echoes
before they had their echoes.

There was a sicker pop cohort of patients
that would tend to receive contrast.

We can see here 43% of patients that received affinity
had a diagnosis of worsening
or clinically unstable congestive heart failure compared
to 31% that had non-contrast echos.

Similarly, acute coronary syndromes were greater in
the contrast echo patients in contrast to those
that didn't receive contrast
and so on for ventricular arrhythmias,
respiratory failure,
and the incidences of pulmonary hypertension.

So in all the definitive patients at the time
of presentation before their contrast echo were a sicker
group than those that had regular non-contrast echoes.

And despite this, there was a significant,
there was no significant difference in
the one day mortality.

So at 24 hours
after hospital admission, the mortality in the patients
that had received affinity was no,
not significantly different than those that had echocardiograms without contrast.

And when subjected
to multi-variable logistic regression analysis,
the patients receiving FIN were 24% less likely
to die within one day than patients not receiving a contrast
agent with adjusted rod odds ratio of 0.76.

So this is a very powerful information
that in those patients that most need
to have the contrast studies to obtain information
for their care, they do not have an increased rate of mortality.

And indeed it appears that their care is enhanced
by the use of contrast when necessary.

FDA Revisions

So, fortunately, the FDA revised the black box labeling
such that on May 12th, 2008, the black box remained,
but the contraindications to contrast agents were restored
to only as in the original labing labeling,
the intracardiac shunt or hypersensitivity issue,
and the 30 minute observation period,
which was recommended for patients.

All patients previously with a black box was removed
to include only those patients with pulmonary hypertension,
which was undefined in the parameters
and unstable cardiopulmonary conditions.

Only these patients are required to have 30 minutes
of observation with vital signs ECG, and O2 sets.

This is not so onerous
because unstable cardiopulmonary patients are generally
in an intensive care unit setting
where they're under constant observation.

At any rate, I will address the issue with respect
to pulmonary hypertension and the guidelines.

Pulmonary Hypertension Considerations

Subsequently, we had the opportunity
to look back into our database of stress echo patients
for those that had had a tr velocity measured so
that we could make an estimate
of their right ventricular systolic pressure.

And we found that of the patients
that had a tr velocity measurement,
there were 16,000 out of the about 26,000 group
that I had mentioned earlier to you.

And of those patients, 6,000 had received contrast.

So the contrast tr measured patients versus the non-contrast
tr measured patients were followed in
the short and long term.

And this actually was retrospective, not prospective.

So we looked back at their short-term
and long-term follow-up,
and we categorized each of these groups
by right ventricular systolic pressure greater than 35
millimeters, mercury greater than 50 and greater than 60,
and we found that there was no association
between increased risk for death or MI
and contrast agent use, despite a higher instance
of clinical comorbidities in the contrast cohort.

And this paper is currently in press
and is available online.

Anaphylactoid Reactions

The unique feature about the contrast ultrasound
anaphylactoid reactions has been postulated
to be a complement activated related pseudo
allergy type of reaction.

And this has been written about by zi
in toxicology.

And the interesting thing is that the IgE mediated type one,
standard type of anaphylactic reaction
and carpa share common symptoms such as angioedema,
asthma attack, bronchial spasm,
and all the things that we rarely can see with
contrast agents.

Contrast agents, not only echo contrast agents,
but this is also thought to be a mechanism for radiology contrast agents.

The unique features of the carpa are
that the reaction can arise at the first treatment
with no prior exposure to the allergen,
and it is thought to be milder
or absent upon repeated exposures.

We certainly, if we see an anaphylactoid
or anaphylactic reaction to a contrast echo contrast agent, we do not readminister the agent in subsequent interactions.

But this is thought to be the characteristic
of the carpa and the reaction spontaneously resolves.

What we do is that if the patient does have a significant serious adverse effect to contrast,
we clearly discontinue the agent.

If it is modest in so far as urticaria,
we will give Benadryl if there is an anaphylactoid
or anaphylactic reaction, again,
in about one in 10,000 patients, this can occur
and you must be prepared for it.

You get the standard approach for care
for anaphylactic reactions with the epinephrine,
Benadryl methylprednisolone if necessary, and observation.

Bio Effects

So regarding safety, we can't be complete
unless we also discuss the possibility of contrast ultrasound generated bio effects.

There are many animal studies
and fewer human studies, which clearly indicate
that at high energies of acoustic pressure, a gas body will cavitate.

And in the early two thousands,
there were several studies which noted that there were
PVCs when patients were exposed
to high MI imaging modalities in the presence
of contrast agents,
and the concern occurred mostly
with the triggered modes.

So in those patients that were evaluated
with a unique and,
and not further commercially developed agent,
significant PVCs were noted.

Again, there has been some discrepancy in some
of the other studies as to whether PVCs were seen or not.

Biomarkers have been evaluated
and found not to be elevated.

In general, the concern regarding PVCs is
noted significantly at only higher myocardial indexes.

So what was published by the American Institute
for Ultrasound and Medicine in 2008 in their executive
summary for the potential bio effects on diagnostic
ultrasound addressed these concerns.

It is recognized that at a high mechanical index,
greater than 0.8, rapid gas body destruction
or cavitation with a potential for bio effects
and particularly manifested as PVCs can occur,
bio effects have not been observed at low mis less than 0.2,
which involve minimal cavitation.

So the recommendations are to minimize the agent dose,
but again, you have to have adequate dose to be able
to have a concentration effect depending on
the purpose of the study as to if it is for LVO
or perfusion to try to maintain the MI less than 0.4.

And certainly our LVO imaging should always be done at less than 0.4.

Because with the real time imaging modalities,
we will have less contrast agent destruction
and much better detection.

So this is perfectly relevant for the everyday on-label use
of contrast agents
and to minimize the ultrasound exposure time.

This relates more to the perfusion assessment,
off-label assessments of myocardial perfusion
with contrast agents when we use depletion replenishment strategies with the high MI impulse
to deplete and a low MI imaging to see the replenishment.

Of course, we will always recommend ECG monitoring
during high MI and myocardial contrast echocardiography.

Again, this relates to the off-label application
and is not necessary during the on-label application of LVO.

However, when we are doing ultrasound examinations,
we always have an ECG monitor available,
so that is not an issue.

Summary

So in summary, regarding the safety
of ultrasound contrast agents
with a specific focus on the cardiovascular applications,
ultrasound contrast agents are extremely safe
with the low incidence of side effects.

They are not nephrotoxic or cardiotoxic.

They, the incidences of hypersensitivity
or allergic events appears to be on the order
of about one in 10,000
and is much lower than current x-ray or Mr.
Contrast agents.

And as in all clinical procedures,
physicians should balance potential clinical benefit against
the theoretical possibility
of associated adverse bio effects in humans.

However, the practical use of contrast agents
for left ventricular opacification is really not of a concern with respect to bio effects.

Thank you so much.