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 This
discussion was moderated by Victor Tapson, MD, Editor-in-Chief
of Advances in Pulmonary Hypertension and Associate Professor,
Division of Pulmonary and Critical Care Medicine, Duke
University Medical Center, Durham, North Carolina. The
participants included Robert Frantz, MD, Assistant Professor
of Medicine, Cardiovascular Division, Mayo Clinic, Rochester,
Minnesota; and John Conte, MD, Associate Professor of
Surgery and Director of Heart and Lung Transplantation,
Johns Hopkins University, Baltimore, MD.
Dr Tapson:
Let’s start with a couple of general comments about
transplantation and pulmonary hypertension. The first
thing that comes to mind is the issue of timing and the
severity of PH.
When is it the right time to proceed with transplantation
or listing?
Dr Frantz:
That’s a timely topic in a situation where the allocation
system for donated lungs may soon be changed by the United
Network for Organ Sharing (UNOS). It is sometimes difficult
to know when to list patients with PH for lung transplant,
especially if they are doing reasonably well with their
current therapy. We tend to have to lead the curve by
a long way because the waiting times for a lung transplant
can be so long. If we don’t think about it at least
a couple of years ahead of time, the patients may be at
risk of dying on the waiting list. The other thing to
keep in mind is that the outcomes in general for lung
transplantation for PH have been inferior to those for
many other diseases, such as COPD, and results seem to
vary some from center to center. There is a need to understand
why it is that some patients with lung transplants don’t
do well if they had pulmonary hypertension as their preceding
diagnosis. We would like to perform lung transplantation
before advanced right heart failure develops because at
that point the risk of the operation may rise. So, for
us, we’re always working on the questions, when
is the right time for lung transplantation, is a lung
transplant adequate or would a heart-lung transplant be
better, and when is it too late?
Dr Tapson:
A few years back we would list patients for lung transplantation
as soon as they were diagnosed with PH. As their illness
progressed, they would end up receiving intravenous prostacyclin,
and several or more years would go by. They did well enough
with this drug that we’d end up inactivating them.
We ultimately realized that we didn’t have to list
them so soon, and we’d start listing them when they
began Flolan therapy, or perhaps a bit sooner. I guess
to some degree it may depend on the center and the patient’s
blood type. If the center has a very long waiting list
or a very short waiting list, the listing time may depend
on those kinds of things.
Dr Frantz: Yes,
no doubt that’s true, and it may vary some from
center to center. I have been impressed that young patients
who have otherwise been healthy can sometimes be surprisingly
well compensated until they are about to fall off the
edge. And then it can be too late in the sense that sometimes
patients can walk 400 or 500 meters with Flolan therapy
and look remarkably well compensated, and then 2 years
later they are just in disastrous trouble, where you are
worried they are not going to survive to transplantation.
Dr Tapson: Because
of its clear association with improved survival, we have
been inclined to rely heavily on Flolan and sometimes,
perhaps, we rely on it for too long. We need to realize
that when someone taking this drug is not doing well,
that we usually have little else to offer. We don’t
have enough data on new drugs combined with Flolan, as
yet. John, when you approach transplantation and the patient
is a pulmonary hypertension patient, is there anything
that would particularly concern you or result in any differences
with regard to your approach to surgery?
Dr Conte:
Definitely. First and foremost, they need to have been
evaluated by someone who treats patients with pulmonary
vascular disease, just because of the things you’ve
been talking about. Most people will do better in your
hands than in my hands. However, oddly enough, the results
of transplantation in our program with pulmonary hypertension
are better than in any other patient group, but it is
not because I do anything differently. I think it has
to do with the fact that we have such good pulmonary vascular
disease folks around. But I certainly think they should
get optimal medical therapy. Back when many of us started
this, there wasn’t much, other than calcium channel
blockers, to treat these patients. Then the prostanoids
came along and boom, we avoid transplantation. Then we
kind of looked at medical therapy as a bridge to transplantation,
and then as we got better and better at medical management,
it became an alternative to transplantation for many patients.
So I think patients need to have a thorough evaluation
and a trial of medical therapy with vasoactive medications.
Certainly, it started off with the
prostanoids, but we have several other options at this
point.
Dr Tapson: John,
when patients come to you ready for transplantation, is
there anything particularly that disturbs you in terms
of hemodynamics? Are there values that make you feel the
patient is too sick? Is there a certain cardiac index
or severity of disease that concerns you about proceeding?
Dr Conte: We
used to say that by nuclear study an ejection fraction
of less than 10% was an indication for heart-lung transplantation.
At every institution that number may be a little higher
or a little lower than that, but I can’t say there
has been a patient in my experience on whom I regretted
doing a lung transplant alone. I had one patient who did
require inotropes for a period of time postoperatively,
for about a month. But that patient was able to come off
inotropes and right heart function has just continuously
improved over the last 2 years. If you can get them through
the operation, there is no advantage in doing a heart-lung
transplant, plus getting a heart and lung is nearly impossible.
With the way the UNOS allocation system is currently configured,
the need for a heart-lung transplantation is a tremendous
disadvantage. To get a heart-lung block you have to be
in the same pool as people with just heart disease. Those
with the highest priority are all in the hospital on various
degrees of support. We currently have a patient who is
status 1-A, the highest priority for the heart people,
in the hospital sitting around waiting for a donor.
Dr Tapson:
John, what about the old single versus bilateral lung
argument? Is there a standard now, or is this still centerdependent?
Are most people doing bilateral lungs?
Dr Conte:
I think most people are doing bilateral lungs, but there
are certain places where they have always done single
lungs and have had fairly good results, and they are going
to continue to do it. I think it boils down to your basic
philosophy. Do you want to treat as many people as possible
with a limited resource, or do you want to try and get
the best results out of every single patient? At about
3 years there starts to be an advantage, regardless of
the etiology of the end-stage lung disease, there tends
to be an advantage in survival with bilateral lung transplantation.
I have always believed that in younger patients I should
do bilateral lung transplants. But quite honestly there
are many young patients who were
near death in whom we did a single lung transplant who
have done very well. I think individual institutions will
tailor their preferences as they see fit, and you can
defend or argue against any position.
Dr Tapson:
So timing might be a concern. If you’ve got someone
really running out of time and you can’t get a bilateral
lung block, but you’ve got a single lung, might
you proceed based on the fact that you’ve got something
available that would be life saving?
Dr Conte:
Absolutely.
Dr Frantz: John,
I am very interested in your perspective about what it
takes to make a pulmonary hypertension patient do well
with transplantation. As you know, the UNOS database shows
a 1-year posttransplant survival rate for patients with
PH to be about 64% compared to about 80% for COPD. This
is causing the UNOS subcommittee looking at lung allocation
to consider requiring PH patients to be incredibly ill
before they receive priority for lung transplantation,
and I think at your center and ours that is not our experience.
The PH patients are young, they often can do extremely
well with transplantation, and it seems that perioperative
management must be critical. What do you think explains
the problem nationally with outcome in lung transplantation
for PH?
Dr Conte:
I think most people in this country who do transplantation
are general thoracic surgeons. And I think lung transplantation
for PH is a cardiovascular disease treatment best handled
by people who are used to handling the heart-lung machine.
All of these people who have significant PH have to be
placed on the heart-lung machine and I think many transplant
surgeons try to avoid that, not so much in patients with
primary PH, but in those with secondary PH. When you do
that you can see severe reperfusion injury when the first
lung sees tremendous pressures during reperfusion and
it gets overcirculated, pulmonary edema develops, and
the spiral starts. So, I think the fact that I am used
to the heart-lung machine and am not afraid of it will
give me a small advantage in taking care of these patients.
Anybody who has a mean pulmonary pressure greater than
40 mm Hg goes right on the heart-lung machine.
Dr Frantz:
Well, I think those are very wise comments and it is my
perception as well that this is the issue, that cardiothoracic
surgeons are used to using cardiopulmonary bypass every
day, and thoracic surgeons don’t do that every day.
They do it maybe when they have a PH patient to transplant.
It has made me wonder, though, if we are potentially going
to change the lung allocation system in a way that might
be detrimental to PH patients because they have the worst
outcome nationally. Maybe we should be talking about designating
centers of excellence for lung transplant for PH and directing
those patients there preferentially.
Dr Conte:
I think you can do that at the grass roots organizational
level where you can verbalize that people with PH have
done very well at these centers. However, from a national
and a regulatory standpoint, there is no way that anybody
is going to allow that to happen. I mean, just like I
may refer someone with a certain disease to a physician
who is very good, I can’t say every patient has
to go to that physician. I don’t see how we can
set it up nationally that PH patients are treated only
at Michigan or Kansas or wherever. Normal referral patterns
will be followed. Then if the people at those centers
say “We’re not great with pulmonary hypertension,
you ought to go to Durham, because Vic Tapson and Duane
Davis are there,” so be it.
Dr Tapson: John,
we want to talk about postop management. Do you and the
transplant pulmonologists manage these folks together,
postoperatively? Do you keep them for a certain amount
of time and then gradually turn them over to pulmonary
specialists? How do you handle this at Hopkins?
Dr Conte:
It’s a team effort all the way, starting with preoperative
management. As the patients begin to deteriorate a little
bit we discuss them more and more frequently, so that
what I might accept as a usable lung for patients when
they are just being plugged into the system will be different
as their condition worsens. We communicate very frequently
preoperatively. Postoperatively, it is a joint management
effort from as soon as they get back from the operating
room until they are discharged from the hospital. It is
only after they are discharged from the hospital that
the medical transplant team takes over. A couple of things
I’ve learned over the years that I think benefit
these patients are maintaining higher peak airway pressures
to try and reduce the amount of interalveolar fluid, interstitial
fluid, and we also tend to try to keep them a bit dry.
If that means they require inotropes or vasoconstrictors,
so be it. I think there is probably a 72-hour period in
which pulmonary interstitial fluid tends to sequester,
and we try to ride patients out through that period with
higher airway pressures. I think that helps shift that
equation of fluid leaving the vascular space and into
the interstitial spaces and alveoli in favor of keeping
it in the vascular space.
Dr Tapson: Do
you think transplant teams tend to have more rigid criteria
or scrutinize PH patients a bit more carefully than other
lung transplant candidates because the risk of mortality
may be higher? For example, in terms of age criteria?
Dr Conte:
From my standpoint, no. We have an age cutoff of
about 60 for bilateral lung transplant patients and I
really don’t think we’ve looked at whether
they would have to have normal PA pressures or not. I
operated on a 61-year-old woman about 21/2 weeks ago who
had sacroidosis, but severe secondary PH, and she did
fine. So, I think you have patients who occasionally might
not do as well, which might lead you to think you shouldn’t
do anybody over age 50. But I think we individualize patients
no matter what their disease process is, so no, we don’t
have anything special for PH patients.
Dr Tapson: How
about for scleroderma and CREST patients? At Duke we’ve
been fairly rigid about who we will do and we very meticulously
screen everyone’s esophageal function, for example,
since we have felt that reflux and aspiration can be a
substantial problem after transplantation, especially
with the associated further reduction in gastrointestinal
motility that you often see. Bob and John, how do you
feel about transplantation in CREST or scleroderma patients?
Dr Frantz: Well,
I think that’s an area where we have to be extremely
careful. These patients may have involvement of the kidneys,
which can be an issue in terms of the toxicity of cyclosporin
after transplantation. Sometimes they can have coronary
involvement as well. They may be undergoing immunosuppression,
including sometimes steroids and other agents, and so
the ability of their wounds to heal and their tissue integrity
may be impaired. Some of them also have substantial problems
with ulceration in their fingers and so forth that might
be a risk for infection. I think we have to be very careful
and certainly more selective in terms of those types of
patients than we would be for a patient with primary PH.
Dr Conte: I
think we do screen them very thoroughly, but I don’t
know if we are any more restrictive. I do think cutaneous
ulcers, if they are active and are not healing, would
rule them out. We’ve performed transplantation in
several patients who had healed ulcers and they had no
more wound problems than anybody
else. too severe to be transplanted in that respect.
Dr Frantz: John,
I’d like to come back to the issues of heart-lung
versus lung transplants and deciding when it is too late
to do lung transplantation in patients with PH. For example,
patients with ascites developing to a substantial degree,
with a low output syndrome, with creatinine levels starting
to climb and we are thinking we need to add dopamine on
top of Flolan to keep them alive, can patients like that
still do well with a double lung transplant? Or, if the
right ventricle is really in great trouble, is it too
late?
Dr Conte: Certainly
I think the postoperative course is going to be a little
bit more difficult and more protracted. But I have performed
transplantation in five patients who had PH and were receiving
inotropes, mostly dopamine, though two actually had dopamine
and dobutamine, and all five of those patients did well.
Now, one patient had a very protracted postoperative course
and required inotropes for about a month, but I don’t
think she would have received a heart-lung transplant
in time, given our organ allocation system. I think if
this were a perfect world and we were taking things off
the shelf, a patient like that would, with no question
in my mind, be better served by a heart-lung transplant.
But that’s not reality. So I think if somebody has
two lungs that are available and they have right heart
dysfunction, they can get through just about anything.
Dr Frantz: In
your hands that is probably true, but I am trying to drive
at why it is that the national outcomes are not so good.
Maybe it has more to do with this issue we talked about
earlier in terms of the use of cardiopulmonary bypass
and being familiar with it. It would be interesting to
look in more detail at the patients who didn’t survive
lung transplantation and see what happened. Perhaps a
multicenter registry effort could help us understand what
the issues really are in terms of outcomes.
Dr Tapson:
I certainly recall 1990 and 1991 when we performed transplantation
in our first PH patients. Although some patients did well,
we didn’t have much experience with prostacyclin
back then. We really respected this disease, as we do
now, but we realized the mortality was high, particularly
with more severe hemodynamics. I wonder if in some cases
we were simply transplanting sooner and that now we have
such faith in prostacyclin that we are more reluctant
to say it is time. It is clear when someone’s condition
is deteriorating and hemodynamics are bad in the face
of prostacyclin that it is time to transplant, but it
would be ideal if there were some way we could recognize
a bit earlier that it is time to transplant. I am not
sure there is a simple way to do that. Here we are starting
to look at the BNP levels in pulmonary hypertension, but
we don’t really know whether these can help predict
if and when someone’s condition is going to deteriorate.
It would be nice to know when the right ventricle is going
to finally buckle and it is time to transplant rather
than waiting for someone to clearly worsen with Flolan.
Dr Conte: I
don’t think we have that. Unfortunately, not enough
people are studying that question to have good data. Certainly,
we’ll never get prospective randomized data, but
I think good clinical data looking at those specific markers
would be helpful.
Dr Frantz: We
do have data from the PH literature published last year
by Dr Sitbon indicating that, for example, patients who
despite having received IV epoprostenol (Flolan) for at
least 3 months can walk less than 380 meters in 6 minutes
have a worse prognosis compared to those who could walk
farther. These patients who despite several months of
IV epoprostenol are still functional class 3+ are clearly
ones we have to be careful to move toward transplantation
much sooner than somebody who can walk 500 meters with
epoprostenol therapy.
Dr Tapson: One
thing we haven’t touched on is cases, for example,
of congenital heart disease, where there are extraordinarily
high pressures, but reasonably good right ventricular
function. It is difficult to go just by the mean PA pressure,
and in terms of timing for transplantation, the same sort
of things apply for walk distance, RV function by echocardiography,
and clinical right heart failure. We have had a few cases
of transplantation based on significant hemoptysis that
has developed and been relatively refractory. Any thoughts
on congenital heart disease patients and the approach
to transplant or timing?
Dr Conte: The
teaching I grew up with was that patients with congenital
heart disease will live forever and you don’t have
to rush as much as you would with those in whom disease
develops later in life. I don’t think I’d
do anything markedly different in their evaluation, with
one exception. For patients with congenital heart disease,
I very frequently get an MRI or an angiogram or an aortogram
looking for aortopulmonary collaterals. It’s the
thing that when you least expect it you’re going
to get into this friable little vessel that’s going
to bleed and cause problems, and that’s the only
thing I do from an evaluation standpoint.
Dr Frantz: Patients
with congenital heart disease tend to have more gradual
deterioration than primary PH patients in general. Some
of it I think is if they have a residual right to left
shunt it may offload the right ventricle and allow them
to avoid problems with right heart failure for a longer
period. So it can make it more difficult to know when
to move to transplantation. For some of them the operative
risk of transplantation is also substantial if they have
had multiple prior operations and, as Dr Conte mentions,
have collaterals in the chest so they bleed a lot at operation.
They may have received multiple transfusions, so they
have high positive panel reactive antibody titers that
make it harder to identify suitable organs. It’s
a complex group that has to be treated in a very individual
way, given the complexity and variety of congenital heart
disease.
Dr Tapson:
I’m sure that it is further complicated by
the fact that
Dr Frantz: I
agree with that. If their ulcers have healed, they should
be OK.
Dr Tapson:
What are the criteria for esophageal dysfunction? That’s
what I’m always told is what precludes them from
being candidates.
Dr Frantz:
If they have a patulous esophagus with very impaired motility
on barium swallow, that is a great concern. I think all
of us have seen problems with patients who have recurrent
aspiration, and in postlung transplantation it can just
be a disaster. So we tend to look at esophageal motility
and often refer to our gastroenterologist to get a feel
for how well the esophagus is functioning. If there is
substantial esophageal dysmotility, that would be a concern
for us in terms of transplantation.
Dr Conte:
I agree wholeheartedly, but I should not even be speaking
on this. Vic, you and your colleagues at Duke have led
all of us in this regard. At the Society of Thoracic Surgeons
meeting a few days ago, one of the Duke residents presented
a nice series of patients where postoperatively people
had esophageal wraps done and had improved outcomes and
decreased OB, am I correct?
Dr Tapson:
Yes, that’s right. We have seen some significant
benefit in that realm and Duane and most of my colleagues
here have been very aggressive in that respect. Our transplant
pulmonologists scrutinize these folks very carefully,
as do your centers. As Bob suggested, if there is a very
abnormal esophagus, there is significant concern going
into transplant. So all of our patients get a very detailed
evaluation with a swallowing study and manometry to make
sure there are not substantial abnormalities. I am not
so sure there is a clear cutoff point of who is some of
these patients cannot get by with a bilateral lung transplant
and VSD repair, for example. Some require heart-lung transplantation,
which makes timing more of a concern as well.
Dr Conte:
The data as to which patients require heart-lung transplants
and which can receive bilateral or single lung transplants
with intracardiac repair are pretty sketchy. I’ve
tended to look at supraventricular problems as repairable
(ie, ASV, PDA), those types of things. Patients who have
anything other than a very simple membranous VSD are those
who need a heart-lung transplant. Those with tetralogy,
single ventricles, or even more complex muscular VSDs
require heart-lung transplantation.
Dr Tapson:
Anything, John, along the lines of right ventricular mechanical
assist devices in the surgical realm that might buy time
or help postoperatively in these patients?
Dr Conte:
We have been looking at a percutaneous right ventricular
support system from a company called A-Med that has recently
been bought out by Guidant and it’s something we
certainly will consider, not just for this patient population
but for those who undergo regular cardiac surgery and
have right ventricular dysfunction.
Dr Tapson: So
that is on the horizon?
Dr Conte: Right.
Dr Tapson: Great.
I don’t think we need to talk about postoperative
issues in any detail since eventually these folks tend
to be similar in terms of management of immunosuppressive
therapy and the like. Any other issues we want to talk
about? Anything else about the UNOS allocation or anything
else that may be worth mentioning in more detail?
Dr Frantz: I
think it’s important that we talk a little bit about
that because the new guidelines for lung allocation are
in flux. I am trying to have some impact on that discussion
by bringing to the attention of the UNOS committee that
the data they are using looking at outcomes do not reflect
outcomes at some centers such as ours and Hopkins. Essentially
the UNOS subcommittee has been suggesting that we give
priority to patients with PH who can walk less than 150
feet, not meters but feet. That’s less than 50 meters.
Those patients are moribund. If we went in that direction,
we might well cause more harm than good by transplanting
in those who are extremely end stage. I am hoping we will
be able to work out a ecommendation that allocation be
made for patients with PH who can walk less than some
other distance. We might pick something like 380 meters
based on Dr Sitbon’s data or 300 meters, or something
like that. It concerns me that the current system appears
to make it difficult for patients with PH unless they
are extremely impaired. I shouldn’t say the current
system. I should say the current proposed system. I don’t
think it will turn out that way because I think we will
be able to modulate the recommendations before they become
working recommendations.
Dr Tapson:
Are you folks seeing the use of septostomy very
often in these PH patients?
Dr Frantz: It
is a situation where, if patients are doing poorly, with
right heart failure despite epoprostenol, then it is worth
thinking about. The issue is that if they have systemic
desaturation on a regular basis, then you are going to
aggravate that with septostomy. Many patients for whom
I have considered it have already had systemic stats that
are low, and I worry that I am just going to aggravate
their hypoxemia. On the other hand, if the systemic stats
are adequate, it can be considered, but in the very patients
where we think about it where the right atrial pressure
is quite high, the cardiac index is low, it is a higher
risk group for not doing well with it. So, honestly, we’ve
not performed it here in any of these patients receiving
epoprostenol.
Dr Tapson: Any
strong feelings about exactly when to list? I should mention
that we usually used to list people when they were initally
diagnosed with PH and learned that that is too soon in
most cases. We generally list now if someone has to have
prostacyclin therapy and sometimes sooner than that.
Dr Frantz: We
have tended to list quite early because the waiting times
have just been remarkably long for lungs. This may be
changing though, in the sense that the one benefit of
the new proposed allocation system is that fewer patients
with emphysema who have relatively preserved FEV1 or whose
risk of dying is relatively low may undergo transplantation.
This might free up some donor lungs to help patients in
even greater need. A very large number of patients with
emphysema receive transplants at variable times in their
disease course, so we have felt the need to list our PH
patients very early.
Dr Tapson:
Is there any penalty for that? Is there some reason centers
might not want to list people and then inactivate and
have a large number of patients on their list inactive?
Dr Frantz:
Well, it is a bit cumbersome because you have this list
that has people on it who aren’t really ready to
proceed with transplantation. It also makes your waiting
times look really long if you are listing people and then
deliberately not doing transplants because they are too
well. Under the proposed new system there may be listing
criteria at the time of listing where those numbers influence
priority, so if you list people early who have relatively
preserved walk distances, they are going to be low priority
for transplant anyway, and you may be better off waiting
until they meet higher priority scores. But we need to
see how the rules are going to work.
Dr Tapson:
Bob, you gave an example of a patient regarding
whether you should do a heart-lung transplant or just
lungs, someone with advanced right ventricular failure
and a lot of ascites. How much does that ascites bother
you? Do you worry that at some point it is more than just
fluid overload, that it is turning into cardiac cirrhosis
and you are transplanting in someone who may now have
substantial liver dysfunction, too?
Dr Frantz: This
issue does come up sometimes. It probably comes up even
more in patients who do not have primary PH. Sometimes
other patients who have restrictive cardiomyopathy or
are waiting for heart transplantation have ascites for
a couple of years and their LFTs are off a bit. In some
of those patients we have done a liver biopsy to make
sure it is essentially a noncirrhotic liver, in order
to be confident that we weren’t going to have a
problem in that way. For most PH patients we have found
that if we treat them with enough inotropes and really
treat them vigorously, we can usually control the ascites.
If we couldn’t control it, I would be quite worried
and might consider liver biopsy in some situations. I
have actually not encountered that yet, where I couldn’t
control the ascites with inotropes and diuretics in a
primary PH patient.
Dr Tapson:
Bob and John, I’d like to thank you both for taking
the time to discuss these issues for Advances in Pulmonary
Hypertension. I look forward to our future interactions.
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