Two Decades of Myocarditis.
I think if I reflect over this period of time, we've become more comfortable managing the
disease.
I think we know how to do it and the survival, as a result, has substantially improved, both
in terms of the acute phase of the disease but in terms of longer-term survival if they
needed bridging to transplantation.
Etiology is still primarily a viral infection, although there's epidemiologic change over
time.
First in the '70s and '80s it was principally the enteroviruses-- Coxsackie in particular.
In the '90s, the adenovirus started to become more prevalent on biopsies.
In the last decade, parvovirus, the herpes viruses, influenza have all started to become
more commonly found on biopsies.
I'm not drawing any conclusions from that.
The geographic and seasonal variations that we know are also unchanged and there are a
number of other causes for acute myocarditis.
Once again, haven't changed over time.
I think we'll see an increasing instance of patients with Lyme disease as that tick-borne
disease moves further north.
The pathogenesis-- I think we have some increasing understanding of this.
And it's the spectrum from acute fulminant myocarditis, acute myocarditis with direct
myocyte injury from the virus, through a subacute phase, and chronic phase is really mediated
by immunological activation and autoimmune activation as well.
We don't know what triggers this cascade in certain individuals and not in others, or
even how to mitigate it at this particular point in time.
But I think we have a better understanding of the pathogenesis of the disease.
Do we have a better understanding of the actual presentation in the phenotype?
This study looked at the large administrative database from 42 hospitals in the US over
a 10-year period.
They found variable presentation of acute myocarditis and couldn't identify a unique
phenotype.
Other than we do know that there is a sort of a variation of the age of presentation.
You can see two main peaks, infancy, early childhood, those first six months to perhaps
18 months, and then in later adolescence.
We know that about 75% of these patients end up in critical care, about 40% get ventilated,
and mechanical support occurs in about 20%.
That gives us some idea as to the resources that are required to manage these patients
and should, in particular, inform the way in which we transfer patients between institutions.
This is work that was led by Ben Sivarajan at Children's Hospital, SickKids, hospital
for sick children last year and looked at 60 patients with acute myocarditis.
The point on this slide is that there is an early recovery phase over the first 12 months,
particularly the first month, I think the median time to start showing recovery was
around 10 days.
But you can see that there is a recovery phase over the first 12 months.
And then a much longer tail where patients may show some signs of ventricular recovery,
but not normalize.
Ben and his group also looked at what are some of the characteristics of these patients,
and the AFM, is the acute fulminant myocarditis, the second group of those with acute myocarditis.
And you can see that there is some difference in age of presentation with acute fulminant
myocarditis, they tend to be younger, more frequently have abnormal vital signs.
The predominant complaint is important.
Acute fulminant myocarditis GI symptoms occurred in about 65%.
So you can see that is presumably related to low output state.
And that can be a frequently missed feature when making this diagnosis.
Whereas in acute myocarditis its more predominant complaint were cardiovascular in effect.
Also those with acute fulminant myocarditis associated with severe ventricular dysfunction
and low output state tend to have a more abnormal chest x-ray.
But both groups have abnormal ECGs and both groups, more on the acute fulminant group,
have arrhythmias.
Let me go back just to this for one second, the abnormal ECG can be anything from low
voltages, through to ischemic changes, through to arrhythmias.
And arrhythmias can be ventricular, they can be isolated, or monofocal, or multifocal VEBs,
or bradycardia.
The point about arrhythmias is that they are-- and we recognize this now-- a very important
sign of doom.
You must pay attention to them.
And in fact, the one study that really reinforces this is a study by Sarah Teele, in Boston,
that demonstrated that arrhythmia on admission is a prediction for ECMO.
So if a patient comes to an institution-- ED a pediatric ICU, that perhaps doesn't have
ECMO facility-- and has a acute myocarditis with arrhythmias, you should be seriously
considering transferring that patient to a place that can do mechanical support.
Arrhythmias are not something that you can usually control, or can often control with
drugs alone, or with pacemaker.
They indicate bad disease and we need to move forward quickly.
The same with biomarkers, so troponins have become much more commonly measured in pediatric
patients over the last 20 years.
And in acute myocarditis there is a huge increase in the troponin level, not just a small amount,
two or three times normal, but a very large increase in troponin level indicating myocardial
injury.
This was demonstrated in the study out of Germany.
And Ben showed this very clearly as well looking at multiples of normal in patients set that
had acute myocarditis.
You can see that sometimes it's over a hundred times normal range is the level of troponin.
Interestingly, and very importantly, it's not an indication though of poor outcome,
in fact, it's the reverse.
It's more indication of perhaps a fulminant state and most patients have a good outcome.
What about ECHO?
Well imaging with ECHO is very important.
It's part of the diagnostic criteria and there maybe a range of abnormalities, from wall
motion, through to thick septum, AV valve regurgitation.
But very important is the LV end-diastolic dimension and this has been demonstrated once
again from SickKids and in other studies that if the z-score, so the diameter of the LV
end-diastolic dimension, is within normal range then early recovery is much more likely.
If it's dilated on presentation, then recovery of that ventricle, the odds ratio for that
is much changed, so that it's an important diagnostic and predictive tool at presentation.
One caution, ECHOs are not without their complications.
And I've seen a handful of patients who have had an ECHO with an operator concentrating
on the screen, hand on a probe doing a subxyphoid approach, not observing the patient, or nobody's
observing the patient, with this such low output state and they get into trouble.
It's not a straightforward diagnostic test, you must have close observation and monitoring.
And this is data once again from Ben that shows that if you present, this light blue
line at the bottom, if you present with a small with a normal end-diastolic dimension
that you usually maintain that dimension for those that have the early recovery.
Those that have late recovery or no recovery start off with a more dilated ventricle to
start with.
Cardiac MRI is often seen as the gold standard.
I'm not certain that that's the case, you can certainly get hemodynamic assessment,
gadolinium enhancement for myocardial edema, hyperemia, and fibrosis.
All of those can be factors helping you with the diagnosis.
And there's a consensus criteria that if two of the three of those are positive then there
is a pretty tight correlation with biopsy.
What about biopsy?
Well, in many respects it's also seen as the gold standard, and in fact, one study that
came out of Korea showed that the biopsy actually had predictive value.
And then if it was a lymphocyte dominant myocarditis, or the presence of fibrosis, then there was
worse longer term outcome.
So there's some value in undertaking these procedures.
If you look at the trends over the last five years, or between five years 2006 to 2011,
in the US-- once again from the large administrative database, the PHIS database-- you can see
that this top line here is the frequency of biopsies and this line here is the frequency
of MRIs so they're crossing over.
The International Society for Heart and Lung Transplantation recently published their guidelines
for evaluation of children with heart failure.
And their recommendations for a cath and a biopsy were not indicated if minimal symptoms.
But it's reasonable to perform it if there is new onset failure, reasonable in patients
when a diagnosis-- a specific diagnosis-- could influence therapy.
Once again, these are class IIa, IIb, with level of evidence being C, so that it's reasonable
to perform but no hard guidelines.
And you have to always balance the risk-benefits for these, and I think we appreciate that.
So taking an infant with myocarditis who is not ventilated, or even on high inotrope support,
to the MRI, and the environment that entails, is not an easy thing to do.
Particularly if they're tachycardic and you're trying to get some sort of gating as well.
So it's not a straightforward procedure.
And same with catheterization the risk for arrhythmia arrest, perforation is a real phenomenon,
and you also get limited biopsy sites.
We biopsy five to seven sites, where it's demonstrated you probably need at least double
that from multi sites to actually make the diagnosis.
So, I'm sorry, this is going to come through in a way that I hadn't anticipated.
So let me just do this.
So the management is still supportive.
Reduce oxygen requirement.
Temperature management is key.
These children often present with shutdown circulation, and core hypothermia.
They're often fretful and agitated, so sedation is sometimes of value.
But you have to be very cautious that we don't overdo that.
Managing preload with diuresis and fluid restriction is very important.
And then it's a monitoring of response.
Question of whether you'd be invasive or non-invasive access always raises it's head, and the risk
of obtaining access can be quite significant.
The same with looking for end-organ dysfunction and biomarkers.
Frequent access to these patients can increase their stress, so making a judgment early on
as to what sort of access they need for blood draws is also very important.
Now respiratory support is interesting, because this is the type of patient that presented
to us not so long ago.
And you can see the green there is the gradual rise in heart rate over a period of time.
Maintain their saturation.
They were tachypneic, but it was pretty stable on non-invasive support.
But you can see this progressive tachycardia.
That's a bad sign.
And you need to be able to trend that over time, not looking at one point in time.
This patient had an event around the time of intubation.
We got to the point where the child was really struggling and needed to be intubated.
And this was a profound drop in heart rate at the time of intubation.
That was all due to the administration of a paralytic drug.
And I think it's an important point that these patients, at the time they lose spontaneous
ventilation is the time they get into trouble.
They have an acute fall in preload to the heart, and that's what precedes this particular
event.
We often worry about the drugs we administer at the time of intubation or induction.
It's the loss of spontaneous ventilation.
And I think being prepared for that's very important.
So it's about anticipation, I think we've learned that lesson over 20 years.
Where the risks are, the cascade of events that fall on from that, and sometimes, inability
to achieve an early return of the circulation.
And understand that these are potentially preventable events.
Now the escalation of management of myocarditis perhaps hasn't changed very much.
We certainly will enhance contractility, reduce afterload if patients are not hypotensive.
Manage rhythm-- once again, be cautious.
You may not be able to control the rhythm at all with the routine drug therapy and pacemaker.
And the introduction of mechanical support.
Well, there are a number of studies that have looked at mechanical support and myocarditis.
This first one by Duncan, both Des and I were co-authors on that paper.
We looked at 15 patients from SickKids and from Boston.
And we had an 87% percent survival of 15 patients.
And these patients were put on ECMO either because they had a cardiac arrest, or because
of their low output state with hypotension.
But you can see, other than this one paper here, the survival of myocarditis is actually
very good on ECMO.
It's the best group.
And they also register in multiple series of ECMO for patients with heart disease.
So early ECMO should be instituted.
There are a number of ways to then approach that.
If you've got fulminant myocarditis and lung injury, perhaps CPR, go to ECMO.
And you can see that most patients with mechanical support early will be ECMO based on this large
cohort study from the PHIS database.
The other decision point, though, is the patient who's got a dilated heart myopathy with slow
deterioration, increasing support, then they may be a group you transition to VAD first,
rather than going down the ECMO pathway.
So the ECMO is certainly the rescue mode.
The question is, "when do you transfer from ECMO to VAD?"
There's limited data available on that, but my experience-- and I think it's supported
by a number of other studies-- is that there's no recovery of ejection within 72 hours and
you're unable to wean the patient from support within seven days, those should be triggers
for you going down the longer term mechanical support.
Often, when you go onto ECMO on these patients, the heart is being stressed to such an extent,
and is so inflamed that, and soon as it's decompressed, it stops.
And there may not be any ejection for a period of time.
And that might take 72 hours to recover, and being patient and waiting for that is really
critical.
Otherwise, you pull the trigger for either listing for transplantation or VAD unnecessarily.
The other thing about these patients is they very quickly develop severe pulmary edema
from left atrial hypertension.
They must go to the cath lab early to be decompressed, promote myocardial recovery, and to reduce
lung injury.
So last point on immunomodulation.
You can see on the slide here from 2006 to 2007, between 60% and an increasing number
up into the low 70% of patients received IVIG for acute myocarditis.
No data to support that management.
In fact, the Journal of Heart and Lung Transplantation in their recent consensus statement said there
is no support at all for corticosteroids or for intravenous immunoglobulin.
There's no value in it.
Don't do it.
So what have we learned in 20 years?
We know they're very fragile patients.
But they have a very high transplant free survival.
We've learned, I think, a better understanding of their phenotype and how to manage that.
It's still primarily a clinical ECG echo diagnosis, with a real value in troponin.
The tradeoffs between the risk-benefit for MRI and cardiac catheterization and biopsy
must always be considered.
LVE diastolic dimension on admission is a good predictor of longer term outcome, and
supportive therapy remains the mainstay.
Beware arrythmias-- early mechanical support.
Thank you.