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 This
discussion was moderated by Roxana Sulica, MD,
Assistant Professor of Medicine, Mount Sinai School of
Medicine, and Director, Mount Sinai Pulmonary Hypertension
Program, Mount Sinai Medical Center, New York, New York.
The participants included James R. Klinger, MD,
Pulmonary Hypertension Center, Rhode Island Hospital,
Providence, and Associate Professor of Medicine, Brown
University Medical School, Providence, Rhode Island; Ronald
G. Pearl, PhD, MD, Professor and Chair, Department
of Anesthesia, and Associate Director, Intensive Care
Units, Stanford University Medical Center, Stanford, California;
and Fernando Torres, MD, Director, Pulmonary Hypertension
Clinic, University of Texas Southwestern Medical Center,
Dallas, Texas.
Dr Sulica: Thank you for joining us for this discussion
today. I’ll start by asking how you would manage a patient
with the following: recently diagnosed pulmonary hypertension,
as suggested by an echocardiogram, with estimated right
ventricular systolic pressure of 90 mmHg, right ventricular
dilatation and severe dysfunction, pericardial effusion,
and an enlarged right atrium. The patient has a systemic
blood pressure of 80/50 mmHg with a heart rate of 120
bpm and is very short of breath with activities of daily
living. There are a few episodes of impending syncope
with minimal exertion for the past two or three weeks.
What would you do or what is your first choice of treatment?
Dr Torres: The first thing I would try to find out is
why the patient developed cor pulmonale. One of the first
illnesses we will try to rule out is chronic pulmonary
emboli. I would try to sort things out very quickly either
by a ventilation perfusion scan or by a CT angiogram.
I would get a chest x-ray and make sure the patient doesn’t
have interstitial lung disease, etc, as an etiology of
cor pulmonale. While I am waiting for other tests, obviously
the patient seems to be in right ventricular failure,
and in such patients we want to make sure to start diuretics
fairly quickly. I usually use furosemide at about 10 to
20 mg per hour even though they are hypotensive. Most
of the time, the right ventricle is able to compensate
better and work more efficiently when the preload decreases.
Another intervention that we tend to do fairly quickly
is to try to get a right-sided catheterization to make
sure the patient has cor pulmonale. This will help manage
the patient. Obviously, with the heart rate of 120 bpm
this may be somewhat challenging, but it is very important
to monitor pulmonary pressures and right ventricular function
in a patient who has hypotension and tachycardia. Most
of the time when I use diuretics in these patients they
seem to stabilize to the point where we can start epoprostenol
therapy. Usually, when the patients seem to be decompensated,
a challenge with epoprostenol, adenosine, or nitric oxide
is not going to be useful given that their cardiac index
is going to be so low that it would be inappropriate to
consider them for calcium channel blocker therapy. A lot
of times, fairly soon, for these patients treatment is
going to be started with a prostacyclin, usually epoprostenol.
Dr Sulica: And your choice is epoprostenol despite the
current availability of other forms of prostacyclins?
Dr Torres: You know, I don’t think there are enough data
on patients with decompensated cor pulmonale, class IV,
for me to feel comfortable enough to start using inhaled
therapy at this point. At this point, the drug of choice
for the decompensated phase of cor pulmonale is intravenous
epoprostenol. Intravenous treprostinil is also available,
but we do not have as much experience using it in acute
right ventricular failure. Dr Sulica: Absolutely. Ron,
do you see placement of a pulmonary artery catheter in
critical care settings as riskier than in patients with
no pulmonary hypertension? Dr Pearl: Certainly placing
a central line in a decompensated patient who is hypoxemic,
is very dyspneic, and may not tolerate lying flat may
have increased risks. I don’t view the passage of a pulmonary
artery catheter by itself as being particularly risky
in a patient with pulmonary hypertension. It may be much
more difficult to do with just pressure waveform guidance,
but we have never had complications from passing the catheter
itself. Obtaining a wedge pressure may not be feasible
in many of these patients, but it may not be particularly
important to measure the wedge pressure because with ventricular
interdependence the wedge pressure may no longer reflect
left ventricular filling. So, people just try to get into
the pulmonary artery and are happy with looking at pulmonary
artery pressures. I think that is being safely done. Dr Sulica: How about the reliability of cardiac output determinations?
Do you confidently rely on thermodilution cardiac output,
given the fact that frequently these patients have significant
tricuspid regurgitation or maybe open PFOs? Dr Pearl:
If there is no intracardiac shunting, and if we are not
talking about a patent foramen ovale, but simply pulmonary
hypertension, our experience has been that the cardiac
output seems to be reliable, and it does provide a useful
trend. We often supplement the cardiac output values by
using a continuous cardiac output catheter with venous
oximetry, or at least getting some intermittent mixed
venous oxygen saturations to be sure that what we think
cardiac output is doing seems to be reflected in the trend
in mixed venous oxygen saturation. I would like to mention
that as the cardiac output gets very low, thermodilution
may be less reliable. Dr Sulica: Great point. What do
you think about the role of transesophageal echocardiography
and transthoracic echocardiography in the critical care
area or intraoperatively? Dr Pearl: In the intensive care
unit we have been extensively using portable transthoracic
echocardiography for diagnosis, but we would use it in
the patient you described to be sure that what we are
dealing with is clearly right heart failure and not from
the insult that has occurred, and that there are no major
valvular abnormalities. We would want to see if there
is shunting going on that we would want to know about.
I think in the intensive care unit setting, transesophageal
echocardiography is likely not all that useful in the
nonintubated patient. I would be concerned about potentially
decompensating a patient as described. In the operating
room it is effective, because we are leaving a probe in
for the entire duration of many of the marked changes
that we might expect to occur. Dr Torres: Do you have
vasovagal episodes during the procedure with transesophageal
echocardiography? Dr Pearl: I think in the nonintubated
patient who is already decompensating I would worry about
it. In the operating room the patient would already be
asleep and anesthetized. Dr Sulica: What do you think
about the reliability of pulmonary artery catheterization
determinations in patients with an acute lung injury or
ARDS (acute respiratory distress syndrome) associated
with signs of right heart dysfunction, low urine output,
or systemic hypotension? How useful and reliable is the
information obtained from placing a pulmonary artery catheter?
Dr Klinger: I think I would approach it two ways. One
is the person we don’t think has pulmonary hypertension
and now has a Swan-Ganz catheter placed for acute lung
injury and is found to have pulmonary hypertension. In
that situation, what we need to stress is that an acute
lung injury normally causes a certain degree of pulmonary
hypertension, so that should be anticipated, not as pulmonary
arterial hypertension, but as pulmonary hypertension secondary
to the acute lung disease. This should resolve as the
lung disease improves. The second situation is someone
who has pulmonary arterial hypertension and then develops
an acute lung injury, and has a Swan-Ganz catheter inserted.
Now the pulmonary pressures may actually be less if the
cardiac output is decreased compared to baseline. High
levels of PEEP will decrease right-sided return and right
ventricular filling, and decrease cardiac output. So the
pulmonary arterial pressure may come down. Occasionally
there will be patients who have high wedge pressure because
they are being volume resuscitated or who have a lot of
pressure transmitted from the airways, causing a falsely
elevated wedge pressure with a true transmural left ventricular
diastolic pressure that is normal. These patients may
appear to have elevated pulmonary venous hypertension
when they actually don’t. So, pulmonary artery pressure
measurements may be confusing in someone that has established
pulmonary hypertension who develops an acute lung injury,
goes on mechanical ventilation and PEEP, and then has
a Swan-Ganz catheter coming in. The other issue to consider
is if patients have enough hypercapnea that they are acidotic.
For any level of hypoxia, pulmonary vasoconstriction is
increased in the presence of acute hypercapnea or acidosis.
So there may be some degree of elevation in pulmonary
arterial pressure in response to acute hypercapnea. I
would add that in many of these settings one can administer
inhaled nitric oxide diagnostically to see to what extent
the acute pulmonary vasoconstriction is really contributing
to any hemodynamic problems. Inhaled nitric oxide can
be effective in blunting the increased pulmonary vascular
resistance from acute hypercapnea. Dr Sulica: So, you
would consider inhaled nitric oxide if the pulmonary vascular
resistance is high? Dr Klinger: Well, it depends on the
type of patient. There is the patient who, as a result
of acute lung injury, has pulmonary hypertension. It is
rarely important to treat pulmonary hypertension in that
situation. Then there is the patient who has established
pulmonary hypertension, who now has a superimposed acute
lung injury and develops worsening of the pulmonary hypertension
because of acute hypoxia, acidosis, or hypercapnea. This
is a very different setting and it is often not easy to
know how much of the pulmonary hypertension in these patients
is actually a problem versus a normal response to acute
lung injury. So, sometimes we debate whether we should
treat the pulmonary hypertension or not. In this setting,
we often use inhaled nitric oxide diagnostically to see
if we can lower the pulmonary pressures. If it is effective
in doing that and cardiac output increases, this can tell
you that the pulmonary hypertension itself is a problem.
Dr Sulica: And you also take into account the level of
the right ventricular dysfunction. Dr Klinger: Definitely!
Dr Sulica: Now, in patients already diagnosed with pulmonary
hypertension who are presenting to the emergency room
hypotensive and seeming septic, what will be the diagnostic
and therapeutic maneuvers? Dr Torres: If they have a fever,
we get a urinalysis, CBC, chemistries, blood cultures,
and a chest x-ray. If we do not identify the source of
the infection fairly quickly, we are going to assume it
is coming from the central line in a patient receiving
intravenous epoprostenol and start intravenous antibiotics.
Dr Sulica: How about giving intravenous fluids when patients
come in septic? Sometimes they are febrile and possibly
fluid depleted. We discussed that we actually diurese
patients in right heart failure even though they are hypotensive.
Dr Torres: For the most part, in patients with pulmonary
hypertension, the right ventricle is not going to need
more preload. We tend just to give them antibiotics, and
we may even have to diurese them, as you are saying. We
check their BUN and creatinine and it is usually higher
than you think. You are right, even though they have a
fever and their blood pressure is a little bit low, we
tend not to give them any fluids. For the most part we
continue giving them their diuretics or just cut back
a little bit on the diuretics. Dr Sulica: And even though
they are hypotensive, you do not interrupt the intravenous
epoprostenol. Dr Torres: Exactly! We never interrupt the
vasodilator therapy because then you may make the hypotension
much worse. Dr Sulica: Jim, do you have the same strategy
of managing these patients? Dr Klinger: Absolutely. I
have very much the same strategy. We have done some laboratory
studies showing that a lot of the catheters are infected
with an organism called Micrococcus, which is a kind of
Staphylococcus, that responds fairly well to treatment
with antibiotics even though you might have to give treatment
for a long period. While commonly considered a contaminant,
Micrococcusshould be treated as a real pathogen in these
patients with indwelling lines. Dr Sulica: What if the
patient becomes hemodynamically unstable? What would be
your favorite inotropic drug and favorite vasopressor,
and what do you think would be the best management strategy
for these patients with pulmonary hypertension in the
operating room? Dr Pearl: It depends a bit on whether
one believes that cardiac output has increased due to
systemic vasodilation versus whether hypotension is due
to a decrease in cardiac output related to very high pulmonary
artery pressures. If the hypotension is directly related
to worsened pulmonary hypertension, I would use an agent
that is inotropic and has some pulmonary vasodilation,
such as dobutamine. Dr Sulica: What do you think about
milrinone? Dr Pearl: I think it is a great drug. However,
it is difficult to start it in a hypotensive patient because
of its systemic vasodilation. You cannot titrate it well.
We use it more when we think we have several hours of
treatment time for careful titration. Dr Torres: I would
echo your comments. I think your preferred therapy depends
on where you were trained or what your subspecialty might
be. If you are a pulmonologist, you tend to use a little
bit more dopamine and if you are a cardiologist, then
you tend to use more dobutamine. As a pulmonologist I
tend to use a little bit more dopamine, especially in
the hypotensive patient. Obviously, I use dopamine at
the expense of patients developing tachycardia. I still
go back and forth between dopamine and dobutamine, especially
in the patient with hypotension. Dobutamine can still
worsen the hypotension and the patient may not tolerate
it. Dr Pearl: The other setting is your sepsis patients,
as you mentioned a little bit before. It is probably a
good example. What has occurred often is not that cardiac
output has fallen from exacerbation of the pulmonary hypertension,
but that there has been some systemic vasodilation and
they are not able to increase cardiac output because of
the pulmonary hypertension. In those settings I am much
more likely to use something that has the ability to give
some inotropic effect and some systemic vasoconstriction,
like dopamine. I am not as worried about adding on pulmonary
vasodilation. Dr Sulica: How about norepinephrine? What
is your opinion about this? Dr Klinger: I think Ron is
right. The difficulty is really not so much treating the
pulmonary hypertension as it is decreasing the drop in
afterload on the systemic side. You need to do what you
need to do to keep up that blood pressure. We do this
sometimes in septic patients as well. When we think their
volume is expanded to the maximum, we try to get away
from volume expansion and go toward vasopressors. I think
people get concerned that when they use vasopressors they
are going to have pulmonary vasoconstrictive effects as
well, but this is really very mild. As a result, once
you have tried the inotropic route, and you fail, vasopressors
would be the next thing to use. I would probably use Levophed.
I don’t know anyone who has tried vasopressin. Are there
some case reports of it now? Dr Sulica: Yes, although
the effect of vasopressin in experimental pulmonary hypertension
is controversial, there are few human case reports showing
that low-dose vasopressin may be used to treat systemic
hypotension with minimal consequences on pulmonary hemodynamics.
How about combining those drugs with direct pulmonary
vasodilator effect, such as inhaled nitric oxide or inhaled
epoprostenol? Dr Klinger: We have tried that infrequently,
but if patients are going to die of hemodynamic collapse
due to sepsis while they have pulmonary hypertension,
I would like to see them treated with pretty high doses
of epoprostenol intravenously, along with dobutamine.
Then, if they are still hypotensive, I would add other
pressors such as Levophed or vasopressin. I think that
is probably the best approach that we have right now.
Years ago, I would try nitric oxide for some of these
patients, but I do not think it has any more vasodilatory
effects than epoprostenol, and it doesn’t have some of
the inotropic effects that epoprostenol has. So, those
would be my three drugs of choice to have on even if the
patient does not survive. Dr Pearl: I do not think there
is any advantage to using inhaled prostacyclin when you
have someone with cardiogenic shock or other kinds of
compromise. The area where we have seen advantages possibly
with the drug’s performance is when we are trying to avoid
hypotension. I don’t think it is going to contribute in
sepsis. Just to clarify, when the patient is acutely hypotensive
it is a pretty difficult setting to start intravenous
epoprostenol. I would think about using an inhaled pulmonary
vasodilator transiently. They usually don’t work in that
setting more than anything else in terms of giving acute
pulmonary vasodilation. I think in a hypotensive patient
it is hard to initially and quickly get to high doses
of prostacyclin. Once you get other pressors and inotropic
agents on, it may be much easier. Dr Sulica: And how would
you look at the response of therapy? Would you place a
pulmonary artery catheter in that situation? Dr Pearl:
I think you probably have to. If you can’t, then you would
be looking at as much epoprostenol as you can start without
the patient becoming hypotensive. It depends on the situation.
If you start epoprostenol therapy, and as you go up, the
blood pressure starts to drop, then you have defined the
maximum dose the patient can tolerate. Dr Sulica: Perioperatively,
how would you manage a patient, let’s say, after having
surgery for valvular heart disease, who still has elevated
pulmonary vascular resistance? Dr Pearl: I think in the
intraoperative and perioperative setting, a lot of treatment
has to be based on defining what goals you are trying
to achieve. Many patients have pulmonary hypertension
after cardiac surgery but do not have problems from the
pulmonary hypertension. You have to figure out if the
problem is they are hypotensive because of low cardiac
output or if there is some gas exchange problem going
on. Where people run into problems is when they treat
the pulmonary artery pressures themselves as the problem.
If the issue is one of low cardiac output without systemic
hypotension, one can often treat that the same way we
would commonly treat low cardiac output, using inotropes
and vasodilators and optimizing the degree of volume.
When we have pulmonary hypertension itself that is clearly
resulting in hypotension, then choices become fairly limited.
In the postcardiac surgery setting, inhaled nitric oxide
has sometimes been useful where we will decrease pulmonary
vascular resistance with the inhaled nitric oxide and
then use additional agents to support both the right and
the left ventricle. Sometimes the severe pulmonary hypertension
is associated with left-sided problems, and you may have
to go to an intraaortic balloon pump, left ventricular
assist device, or sometimes a right ventricular assist
device. It is hard to make broad generalizations on how
to treat the perioperative pulmonary hypertension. The
point I would emphasize is that often people get into
trouble trying to treat it, when in fact it doesn’t need
to be treated. We need to be sure that we identify what
we are trying to improve. Dr Sulica: How about preoperatively,
for example, in patients with valvular disease or patients
evaluated for heart transplantation? Do you have a cut-off
of the preoperative pulmonary vascular resistance to proceed
with surgery? Do you test for so-called reversibility?
Dr Pearl: If you are now talking about cardiac surgery,
there are two very different settings, the patient who
is having definitive repair of mitral valve disease or
coronary disease, versus the patient who is having a heart
transplant. In patients who are having corrective cardiac
surgery, I think we are relatively liberal in allowing
pulmonary hypertension when they have a compensated right
ventricle. We are doing something that will eventually
improve the outcome. We may have to temporarily support
the right and left ventricle with pharmacologic and mechanical
means, but normally when the cardiac problem is repaired,
over time we will see things improve. Those are the patients
in whom we may postoperatively use inhaled nitric oxide
and transition to a phosphodiesterase- 5 inhibitor such
as sildenafil. In contrast are the patients who are having
heart transplants where there is a high resistance pulmonary
circulation, and we are putting in a donor heart that
has no right ventricular compensatory mechanisms, and
so for those patients, yes, we do consider pulmonary hypertension
to be a contraindication to the surgery. In terms of the
exact numbers, I think it is a combination of the pulmonary
artery pressure, the gradient between mean pulmonary artery
pressure and wedge pressure, the pulmonary vascular resistance,
and the reversibility with pulmonary vasodilator therapy.
I hesitate to give exact numbers because it is often the
combination of them that we decide on, rather than using
one specific number. Dr Sulica: In terms of testing the
vasoreactivity and reversibility, what agents are you
using? In the catheterization lab when you test for vasoreactivity,
if we have a patient with high wedge pressure we are reluctant
to use inhaled nitric oxide or epoprostenol, being mindful
of pulmonary edema. Dr Klinger: We are always concerned.
We actually had two patients whose cases we published
years ago who developed acute pulmonary edema in a response
to inhaled nitric oxide. They had wedge pressures that
were pretty normal. They both had scleroderma, and we
think they just had stiff ventricles and couldn’t handle
it. On the other hand, we have a plethora of patients
with long-standing congestive heart failure and diastolic
dysfunction who we are called to see because they have
pulmonary hypertension that appears to be out of proportion
to their wedge pressure. In some cases, I have actually
done vasodilator trials and have seen improved pulmonary
pressure without an increase in the wedge pressure. What
we generally try to do is to get as much diuresis as possible
and get the wedge as low as possible. Then after that
we will try to add a pulmonary vasodilator. In that situation,
I think nitric oxide is really the best because, if we
do see a rise in wedge pressure, we can turn it off pretty
quickly and resolve the problem. Dr Sulica: Although there
are reports of pulmonary edema in patients with underlying
left heart dysfunction, even with inhaled nitric oxide,
it has a much shorter action, so you hope it is going
to reverse faster. Dr Klinger: I think it is a very interesting
area of pulmonary hypertension that we don’t have a lot
of data on. There are some people with elevated wedge
pressure in whom we are hesitant to do vasodilator trials,
yet other patients seem to tolerate it fairly well, and
I don’t currently have a good way to differentiate what
is going to happen. Dr Torres: At the same time, should
we be doing a vasodilator challenge in a patient with
a high wedge, or should we measure a left ventricular
end diastolic pressure to confirm that this was an accurate
wedge? Dr Sulica: Absolutely! It might sometimes be impossible
to determine an accurate wedge in patients with pulmonary
hypertension, at least severe pulmonary hypertension.
Ron, are these issues still valid for the patient we were
just discussing with high pulmonary vascular resistance?
Presuming that there is a left heart failure so the wedge
is high, are you concerned about putting the patient in
pulmonary edema with the vasodilator challenge? Dr Pearl:
The preoperative testing concern is that the pulmonary
vasodilation allows the right heart to overload the left
heart because the patient is already in a volume overloaded
state. In essence, the pulmonary hypertension is a protective
mechanism. Our experience has been that there is less
concern in the outpatient setting for the heart failure
patient than in past years because these patients are
so much better managed clinically now than they used to
be. They have less volume overload and we don’t precipitate
a lot of pulmonary edema with the challenge. In the acute
intraoperative and postoperative setting we are normally
very actively titrating volume, and although it is conceivable
that the nitric oxide would produce the same effect of
producing pulmonary edema, I think it is less likely to
occur because we are often very focused on maintaining
the appropriate volume status. Dr Sulica: Great. Thank
you Ron, Jim, and Fernando. I really appreciate your time.
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