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 This
discussion was moderated by Ronald J. Oudiz, MD, Associate
Professor of Medicine, David Geffen School of Medicine
at UCLA, and Director, Liu Center for Pulmonary Hypertension,
Division of Cardiology, Harbor-UCLA Medical Center, Torrance,
California. The participants included Michael J. Krowka,
MD, Professor of Medicine, and Russell Wiesner, MD, Division
of Pulmonary and Critical Care Medicine, Mayo Clinic,
Rochester, Minnesota, and Michael Ramsay, MD, FRCA, Chairman,
Department of Anesthesiology and Pain Management, Baylor
University Medical Center, and Clinical Professor, Department
of Anesthesiology and Pain Management, University of Texas
Southwestern Medical Center, Dallas, Texas.
Dr Oudiz: How are
most patients diagnosed with portopulmonary hypertension?
How many patients have their condition discovered “by
accident” in the operating room as they’re
being prepared for
liver transplantation?
Dr Ramsay: Up until
about 18 months ago we diagnosed about 60% of these patients
on the operating room table just prior to transplant.
Now, because everybody is looking for it, all our patients
are being screened with echocardiography, so we’re
diagnosing only about 15% to 20% on the operating room
table. Those are the patients who have had normal echos
sometime in the past year during the work-up, but developed
portopulmonary hypertension since then.
Dr Wiesner: We’ve
always been screening. Our pickup in the operating room
is probably less than 15%, isn’t it?
Dr Krowka: It’s
fairly low because we’ve been very aggressive with
the screening. We’ve tried to screen so there are
never more than 12 months between echos, but we still
miss the few that get to the operating theater. But we
have the back-up of their having a Swan-Ganz catheter
placed at the time of the operation. So if we missed something
during screening, we hope to pick it up at the time of
operation.
Dr Wiesner: Most
of these have been moderate cases. I don’t know
if we’ve missed any severe ones.
Dr Krowka: We have
not had to cancel any cases in the last 8 years that I’m
aware of.
Dr Wiesner: We’re
talking about pulmonary pressures
of 40 mm Hg or so, or 35 mm Hg.
Dr Krowka: A mean
pulmonary pressure certainly greater than 50 mm Hg. We
screen routinely for portopulmonary hypertension—every
case at our institution, symptomatic or not, gets a screening
Doppler echo at the time of transplant evaluation. I’d
say 10% of the candidates have a right ventricular systolic
pressure estimate greater than 50 mm Hg, and all of those
patients undergo a right heart catheterization.
Dr Oudiz: So if the
right ventricular systolic pressure is less than 50 mm
Hg, you don’t necessarily worry about significant
pulmonary hypertension?
Dr Krowka: That is
correct, but we follow through and probably repeat an
echo in 6 months if, let’s say, the patient had
a right ventricular systolic pressure of at least 40 mm
Hg.
Dr Ramsay: That’s
similar to what we do at Baylor, but I’d like to
follow up on one comment about canceling patients on the
operating room table. I’d like to change that to
“delay” or “defer.” We bring everybody
back later, having treated them with vasodilators for
up to 18 months, and transplant
successfully.
Dr Oudiz: So a good
percentage of those who were initially found too risky
for surgery were treated, and a good number of them were
brought back and successfully underwent transplantation?
Dr Ramsay: Correct.
Dr Oudiz: Dr Krowka,
does your experience match that of Dr Ramsay’s with
respect to patients who might have had a normal echo a
couple of years prior to their transplantation and then
developed pulmonary arterial hypertension?
Dr Krowka: Absolutely.
We found several cases where there was a normal screening
echo, not only in terms of estimated right ventricular
systolic pressure but also normal right ventricular size
and function, and 12 to 18 months later at least moderate
pulmonary hypertension developed by all recognized criteria.
So this can change relatively quickly.
Dr Ramsay: We had
one patient in whom severe pulmonary hypertension developed
in 3 weeks. He had a normal echo 3 weeks prior to coming
to transplant, and then had a mean pulmonary artery pressure
of about 45 mm Hg at the time of transplant. We went back
and reviewed the echo and, maybe in hindsight, we could
look at it and say there may have been some signs that
the right ventricle was under strain, but not definitely.
It was basically a normal echo. There had to be some kind
of acute thrombosis or thromboembolic etiology, you would
think.
Dr Oudiz: It is fascinating
that you have the opportunity to screen a relatively small
group of patients that allows you a window into the development
of pulmonary hypertension. In patients with connective
tissue disease or primary pulmonary hypertension or drug-induced
pulmonary hypertension, the denominator is too large to
screen them all and assess development, so we don’t
have a good feel for how quickly pulmonary arterial pressures
rise from a baseline of normal. But here you’ve
put a finger on the natural history of patients as they
develop pulmonary hypertension, and sometimes catch it
before it evolves. Three weeks is really strikingly quick.
Even a year and a half is much quicker than what is generally
thought to be the time course of pulmonary hypertension
development. In portopulmonary hypertension patients we
think it takes years to decades.
Dr Krowka: I agree
that when these things occur this quickly a strong possibility
exists that we’re dealing with some in situ thrombosis
as opposed to their throwing clots or just obviously missing
something on echo. Indeed, we’ve seen a spectrum
of pathology at autopsy. There’s no question that
platelet aggregates and in situ thrombi have been seen,
at least in the setting of post-transplant pulmonary hypertension.
Dr Ramsay: That’s
an interesting point, Mike. We certainly see 10% to 15%
of liver transplant patients who come through for surgery
who, despite having a significant coagulopathy on laboratory
analysis, when you run a thromboblastogram, they’re
actually hypercoagulable. This is particularly seen in
patients with primary sclerosing cholangitis (PSC) and
in some with primary biliary cirrhosis (PBC). This may
be a factor that sets them up to present more acutely
with raised pulmonary artery pressures.
Dr Wiesner: When
we look at our group, there’s no etiology that seems
to stand out. We see it as often in alcoholic patients.
Dr Ramsay: The numbers
of hypercoagulable patients are small. The number of patients
with PSC who have the typical hypocoagulability compared
with the number of patients who are found to be hypercoagulable
in practice is not many.
Dr Oudiz: What happens
when a patient is scheduled for liver transplantation
and is found either on the operating room table or just
with a screening echo? Clearly if the pressure is high,
you're going to send that patient to right heart catheterization.
And those who by right heart catheterization have significant
pulmonary hypertension that precludes surgery will likely
be placed on treatment. What percentage of those treated
patients with PPH-like disease can actually get
their transplant?
Dr Ramsay: So far
in our patients we’ve gotten very aggressive in
treating them; we’ve performed transplantation in
everyone we have deferred. We have not lost anyone on
the list while they’ve been receiving therapy. But
the thing that we look for is not just mean pulmonary
artery pressure and pulmonary vascular resistance. We’re
also looking at right ventricular function. So they’re
getting right heart catheterization and echocardiography
relatively frequently, every 3 to 6 months. We’ve
had two patients in whom the right ventricle really toughened
up. Instead of having a widely dilated ventricle and right
atrium, we’ve seen that ventricle turn in a period
of 18 months into a good contracting hypertrophied ventricle.
So we took those patients on—we couldn’t get
their pressures below a mean of 45 mm Hg, but the patients
did fine.
Dr Wiesner: What
are the ranges at the higher end? Are any of these in
the 70, 80, or 90 mm Hg range?
Dr Ramsay: The highest
mean pressure in the true portopulmonary hypertension
patient (we’ve seen higher numbers in patients with
cardiomyopathy and volume overload) we’ve seen that
I can recall is probably 58 mm Hg. But that was pretransplantation.
In that patient, after reperfusion of the new graft, we
got a massive increase in cardiac output. That patient’s
mean pulmonary artery pressure was equivalent to the mean
systemic arterial pressure.
Dr Oudiz: The mean
pulmonary pressure went up.
Dr Ramsay: Yes. With
the increase in flow and relatively fixed pulmonary vascular
resistance, the pulmonary artery pressure went up. That
was several years ago. We eventually lost that patient.
We probably in retrospect could have put a right heart
assist device in that patient or something like an atrial
septostomy would have been required.
Dr Krowka: We’ve
had a few cases also where we identified during the evaluation
the mean pulmonary arterial pressure being greater than
50 mm Hg on right heart catheterization and we initiated
appropriate therapy with intravenous epoprostenol and
had disappointing results. Either there was no significant
improvement in hemodynamics over 6 to 12 months or a substantial
adverse event occurred, usually related to the hepatic
status. They had a bleeding episode, they got infected
and died of a nonrespiratory or noncardiopulmonary complication.
So not everyone we’ve seen previously has been a
responder. Most of them have responded and we still have
several on the waiting list for transplant, but unfortunately
other bad things can happen.
Dr Ramsay: When you
say they’re not responders, have they progressed
or have they stabilized at whatever level you saw?
Dr Krowka: That’s
a good point. They’ve stayed right where they are.
We’ve not been able to dramatically improve their
mean pulmonary artery pressure or their pulmonary vascular
resistance. Now, recently we’ve noted when we followed
Btype natriuretic peptide levels that the levels decrease,
but the hemodynamic numbers stay about the same, and I’m
not sure what that means—that could be favorable—but
certainly the hemodynamics by number are not worsening.
Dr Ramsay: That’s
not the natural history of the disease. If you don’t
treat it, it’s going to continue to progress. Therefore,
you have stabilized it. We’ve seen two patients
now with that right ventricle over the course of 18 months
that has looked a lot stronger, strong enough that we’ve
elected to take them on and perform transplantation.
Dr Oudiz: Dr Ramsay,
in the patients you are treating, are you also treating
solely with intravenous epoprostenol?
Dr Ramsay: We have
been administering intravenous epoprostenol as our primary
therapy until this last year and a half. We have now looked
at other therapies that don’t require the intravenous
route. Some of the patients are getting bosentan despite
the fact that it has a reputation for kicking up liver
enzyme levels. We’ve got a pulmonologist who is
administering it in preference to epoprostenol. We also
have a limited experience with treprostinil.
Dr Krowka: We’ve
used subcutaneous treprostinil rather than intravenous
epoprostenol in four patients waiting for transplantation.
Dr Oudiz: Dr Ramsay,
I think you mentioned that one of your end points in
addition to the standard ones is right ventricular function.
Dr Ramsay: The right
ventricle is the critical piece in this. If the pressure
is high but the right ventricle is great, that patient
ought to do fine.
Dr Oudiz: You will
do a transplant in a patient whose right ventricular function
has improved but the mean pressure is still over 50 mm
Hg?
Dr Ramsay: Yes, but
the right ventricle really has to be good, we have to
see it really contracting well. In most of those patients,
when you initially see them, the right ventricle is widely
dilated and the right atrium is widely dilated. So even
if they were to survive the surgery, that liver graft
gets congested because of the right ventricular dysfunction.
And the liver will fail. So we really must have good right
ventricular function proven by preoperative and intraoperative
transesophageal echocardiography.
Dr Oudiz: Dr Krowka
and Dr Weisner, do you have the same criteria or do you
have absolute cutoffs in terms of pressures?
Dr Krowka: I think
we’ve used essentially the same criteria. A 50 mm
Hg mean artery pressure is the number we’ve followed
with our anesthesia group and we do want to see improvement
with epoprostenol and the right heart function. I agree
that right heart function is absolutely critical. Our
anesthesiologists would follow right heart function in
the operating room with transesophageal echocardiography.
I don’t think there’s any patient we’ve
let go to liver transplant who has not been covered by
at least intravenous epoprostenol, so we want to have
a vasodilator on board for those who have a significant
pulmonary hypertension situation.
Dr Wiesner: At least
not in recent times.
Dr Krowka: Correct.
Dr Oudiz: What outcomes
do you see on average when patients who had pulmonary
hypertension were treated with, let’s say, intravenous
epoprostenol, and had, for example, their mean pressure
drop to 40 mm Hg? How do they do postoperatively and how
do they do over the longer term?
Dr Ramsay: At Baylor,
we’ve had one patient and this is the last one we
lost postoperatively, someone who came in with a mean
pressure in the mid to high 50 mm Hg range. We were able
to reverse it on the table by just using inhaled nitric
oxide. We brought that patient’s mean pulmonary
artery pressure down into the low 40 mm Hg range and we
felt comfortable that we could transplant safely. The
right ventricular function looked reasonable. We transplanted.
However, in a very small number of transplant patients
in our practice, in about 3%, on reperfusion the cardiac
output increases up to 300%. That’s what happened
in this patient. Cardiac output went up from 6 liters
to nearly 18 liters per minute and with that massive increase
in cardiac output, the mean pulmonary artery pressures
went sky high and the right ventricle failed. So we’d
rather back off and take some time to get that pressure
down and make sure it stays down and that right ventricular
function is good, before we go ahead.
Dr Krowka: At Mayo
we would treat these patients with intravenous epoprostenol
or subcutaneous treprostinil for several months before
transplantation, continuing the medication through the
procedure. After transplantation it’s a clinical
judgment as to how quickly patients can be weaned off.
With the last three patients that I am aware of, we were
able to wean off over several months and within one year
after the transplant. I’m not sure if we’ve
cured portopulmonary hypertension. I think we’ve
controlled it and improved it, but it’s unclear
whether we actually normalized the hemodynamics after
transplant in everyone. The other benefit pretransplant
was not only the pulmonary vasodilator therapy but some
pulmonary vascular remodeling, hopefully, and an antiplatelet
aggregating effect.
Dr Wiesner: We’ve
had some deaths on treatment too. Early deaths. My feeling
overall is that I’m not sure how often liver transplantation
per se actually reverses the condition. I know it’s
been reported. Mike, have we seen anybody where it’s
been completely normalized?
Dr Krowka: We’ve
dramatically improved patients’ hemodynamics, but
I’m not aware of any patients at our institution
that we’ve been able to take absolutely off all
pulmonary vasodilator therapy, and that includes a calcium
channel blocker, after transplantation. The patients we
have posttransplant now are being treated either with
a calcium channel blocker because they’ve had some
systemic hypertension or with bosentan. No one is receiving
intravenous epoprostenol or subcutaneous treprostinil
post-transplant at least after a year. We’ve been
able to wean everyone off it.
Dr Ramsay: It’s
somewhat similar at Baylor. We’ve had to keep giving
some patients intravenous epoprostenol for over a year,
for almost 18 months, before we’ve gotten them off.
But we’ve had a small number of patients whose condition
reversed in a matter of days, and you just wonder if it
is a different pathology that we are dealing with.
Dr Wiesner: Have
you had some deaths?
Dr Ramsay: Yes, before
epoprostenol we did. They were mostly postoperative as
the pulmonary artery hypertension continued to progress
despite transplantation. But once we instituted epoprostenol
therapy postoperatively until stabilization or normalization
of pressures, we have not had a death as a result of pulmonary
hypertension.
Dr Oudiz: That’s
fantastic. The fact that you can get everyone off prostacyclin
therapy, even if it takes a year and a half, is quite
different from what we’ve seen with the pulmonary
hypertension patients. That brings us to the last question.
Dr Krowka, you had a concern and we all have concerns
about what the future holds in terms of therapy. We mentioned
bosentan, which is certainly off label in patients who
have liver disease, and also sildenafil, which is looking
promising and undergoing multicenter trials. What do you
think about the use of these as primary agents with respect
to initial treatment once the patient has been screened
and found to have pulmonary hypertension?
Dr Krowka: There
is substantial potential for bosentan if it’s given
with careful attention to dosing and watching liver function.
I would continue to use the prostacyclins, and perhaps
combination therapy is going to be a good idea down the
road. I have concerns about sildenafil mainly because
some patients with liver disease probably have increased
nitric oxide effect on the vascular bed already. If one
thinks sildenafil is working because of increasing nitric
oxide effect even further, I am not so sure that medication
is going to be appropriate alone or in combination for
portopulmonary hypertension. We would have to do the studies.
I think combination management may well be an option and
I would not exclude bosentan as Mike Ramsay said.
Dr Ramsay: I think
the inhaled nitric oxide issue is interesting. In the
first six patients we tried it on we got no response at
all. We even looked at exhaled nitric oxide and in some
of the patients it was very elevated, but in others it
was normal. Then we had a series of five patients where
inhaled nitric oxide helped. Inhaled nitric oxide in these
patients clearly brought the pulmonary artery pressures
down temporarily. I’m wondering if the same thing
might be true of using sildenafil. You might find in some
patients it works and in some it may not work.
Dr Krowka: That gets
back to your comment on pathology. There is probably a
spectrum of pathology that we are seeing, not just one
pulmonary vascular pathology. And that is something we
can hopefully learn more about over time.
Dr Oudiz: Is a heart-lung
transplant a viable option in some patients?
Dr Wiesner: It is
for certain people. For younger people I think it is a
consideration.
Dr Krowka: There
have been two adult heart-lung-liver transplants accomplished
in the United States. Both were done in the Mayo Clinic
system for primary biliary cirrhosis and severe pulmonary
hypertension. We have not done any more because multiorgan
transplantation is just such a major undertaking and it’s
so hard to pick the right recipient. Our selection criteria
have required that the patient had to be under 50 years
of age. So right way you’ve narrowed such transplantation
down to a very few patients.
Dr Oudiz: What are
your thoughts on the possibility of a small, multicenter
trial looking at initially the use of bosentan vs Flolan
or Remodulin in patients who were screened and deemed
to be inoperable because of their pulmonary hypertension?
Dr Krowka: I agree
that it should be done. Anecdotally, several institutions
are using the medication carefully but we’ve not
been able to conjure up enough support to provide the
medication in a multicenter trial. Perhaps we need to
revisit this again as other investigators present their
case-by-case successes. A case report from the United
Kingdom will be published in Transplantationregarding
the beneficial effects of bosentan after transplantation
in a patient who did not respond to intravenous epoprostenol.
Dr Wiesner: Mike,
are enough data published to put ours together with other
groups? There are only anecdotes in this literature, right?
Dr Krowka: You’d
really have to have a multicenter study where the inclusion
criteria and outcome variables are well defined.
Dr Ramsay: I think
now enough people are screening ahead of time that maybe
we could get the numbers in a multicenter study and do
this.
Dr Oudiz: Is there
anything else that you think is critical or at least useful
that we haven’t discussed?
Dr Ramsay: What’s
the downside of going ahead? What happens to patients
if you go ahead and transplant with significant portopulmonary
hypertension? It’s twofold. One is that if you have
acute right ventricular failure, you may lose the patient.
Two, if you just have right ventricular dysfunction, you
may lose the graft, which may mean losing the patient
too. So there are two downsides to going ahead. It’s
not just patient survival, it could be graft survival.
Dr Krowka: I think
all the centers need to continue to be very aggressive
with their screening because new medication options are
coming down the road. Even inhaled iloprost may be a therapeutic
option. The door is open for us not only to consider these
options but also to initiate a multicenter approach toward
therapy.
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