WSPF – “Pulmonary Hypertensive Vascular Disease: Pathobiology & Treatment” with Jeff Fineman

WSPF – “Pulmonary Hypertensive Vascular Disease: Pathobiology & Treatment” with Jeff Fineman

August 29, 2019 1 By Bertrand Dibbert


Welcome to World Shared Practices Forum. I’m
Dr. Jeff Burns, Chief of Critical Care at Boston Children’s Hospital and Harvard Medical
School. We’re very pleased to have with us today Dr. Jeff Fineman. Dr. Fineman is Professor
of Pediatrics at the University of California in San Francisco and Chief of Pediatric Critical
Care at the Benioff Children’s Hospital in San Francisco. Jeff, welcome. Thank you very much. It’s an honor to be here
and be part of such a tremendous forum that you have here. Jeff, you are widely considered to be one
of the most focused researchers in the field of pulmonary hypertension in our field of
pediatric critical care. You’ve lectured all over the country and indeed all over the world
on this. And many of my colleagues are undoubtedly wondering, how can we think about pulmonary
hypertension? What are the latest thoughts about the state of the research and how we
approach patients at the bedside? And so I’ll begin simply by saying where do we begin?
How do you think about pulmonary hypertension? Well, Dr. Burns, as you know, this is a, it’s
a complex disease. It can be a disease that’s the primary problem or it can be associated
with many other disorders. Some of them we’re just figuring out. And so it’s complicated.
Because it crosses over many different disciplines. And probably the pathobiology is quite diverse.
And then within pediatrics, it really brings up some special circumstances that really
aren’t reflected in the adult population. So I think we have to kind of readdress, reconsider
some of the fundamental things that we think about with pulmonary hypertension. So for
example, let’s start with the definition. So the definition is a hemodynamic definition,
even though it’s a structural and functional disease of the pulmonary vasculature and ultimately
the right heart. We have a hemodynamic definition, which is mean pulmonary arterial pressure
of greater or equal to 25 millimeters of mercury at rest or 30 millimeters of mercury during
exercise and a calculated pulmonary vascular resistance of three woods units or greater. So unfortunately, that definition may work
reasonably well for the adult population. But there are several circumstances where
it doesn’t really adequately characterize the disease in the pediatric population. One
most notably would be patients with single ventricular heart disease, where as you know,
since they ultimately go on to have a passive pulmonary blood flow system, any modest elevation
in pulmonary vascular resistance can have a profound clinical impact on their outcome
and potential surgical candidacy. So we really have to rethink that. So we’re
even rethinking the name, in fact. Instead of pulmonary hypertension, we’re often thinking
about it now as pulmonary hypertensive vascular disease without the strict definition that’s
related to hemodynamic parameters. The other thing is, it’s pulmonary vascular
resistance. And the adult population tends not to index the cardiac output to body surface
area, where in pediatrics, we do. So a PVRI, or an index pulmonary vascular resistance
can be quite different than a non-index, particularly in our teenagers where the weights may be
the same as an adult, but we’re indexing it and they’re not. So I think we have to start with the definition
and really rethink how it relates to pediatrics. So we’re getting away from that catch-all
phrase of pulmonary hypertension and really talking more about pulmonary hypertensive
vascular disease. Well, Jeff, I have to confess I’m glad to
hear a reconceptualization of this. Because it’s never made sense to me that a 3-year-old,
a 30-year-old, and a 60-year-old all had the same diagnostic criteria. And it just intuitively
didn’t make sense. And I can’t think of any other parallel in our field of pediatric critical
care where we anchored an adult definition to an infant or a child. But if that’s the
case, then what is the classification scheme that we should be thinking about for these
pulmonary hypertensive vascular disorders? That’s an excellent point. So there is an
adult classification that was modified in 2013 at a conference in Nice. And it certainly
is getting better than what it was in terms of incorporating the pediatric world. For
example, the portion related to congenital heart disease is much better. As you can see, it’s classified in five groups,
with the first one being pulmonary arterial hypertension with the major group being the
idiopathic or what we would call primary pulmonary hypertensions, both hereditable and non-hereditable.
But within that group as well is a big sub-population of the pediatric pulmonary vascular disease,
which would be congenital heart disease. And in addition, there’s also persistent pulmonary
hypertension in the newborn, which as you know is vastly different than the disease
related to congenital heart disease. The second subgroup is pulmonary hypertension
due to left heart disease with subset of having congenital deficits, defects in that. The
third group is pulmonary hypertension due to lung disease and/or hypoxia. So within
the pediatric world, the emerging group of patients with chronic lung disease and bronchopulmonary
dysplasia could be characterized in that group. And the fourth group is chronic thromboembolic
pulmonary hypertension. And then the fifth group is pulmonary hypertension with unclear
or multi-factorial mechanisms. So that’s what we have to work with from an
adult classification perspective. Let me show the next slide, which does show you an improved
classification with a subset related to congenital heart disease. So in terms of the updated
classification of pulmonary arterial hypertension associated with congenital heart disease,
you can see that there’s now four sub types, the Eisenmenger syndrome, those with the left-to-right
shunts, both correctable and non-correctable, pulmonary arterial hypertension with coincidental
congenital heart disease, which is an interesting subpopulation, and those with postoperative
pulmonary arterial hypertension. Those with congenital heart disease that was repaired
but then go on to have pulmonary arterial hypertension that’s progressive. However, as you can see, this really falls
short when we’re talking about classifying pediatric pulmonary vascular disease. Because
it really doesn’t take into account a multitude of issues related primarily to pediatrics,
that being some of these subsets of patients have chromosomal or genetic syndromes associated
with their disease. There’s obviously developmental abnormalities
with a lung hypoplasia being a major one. That’s a significant population. Other multi-factorial
conditions. And then probably most importantly, it fails to take into account pathological
insults in the growing lung, whether it be in utero aberrations and postnatally. As you
know, the lung can be insulted postnatally and then fail to grow adequately. And so my colleagues got together a few years
ago at the Pulmonary Vascular Research Institute meeting in Panama. And a task force was put
together. It’s an ongoing task force. But we put together a modified classification
for pediatrics that really starts to get at some of these more developmental based problems. So you can see there’s 10 major categories.
The first is prenatal or developmental pulmonary hypertensive vascular disorders. A subset
of PPHN may be incorporated into that category. There’s a perinatal pulmonary vascular maladaption
which is another subset of persistent pulmonary hypertension in newborn. Pediatric cardiovascular
disease, which incorporates the congenital and acquired heart disease. Bronchopulmonary
dysplasia, isolated pediatric pulmonary hypertensive vascular disease, or isolated pediatric pulmonary
arterial hypertension, which would take place of the idiopathic pulmonary hypertension,
multi-factorial pulmonary hypertensive vascular disease and congenital malformation syndromes,
pediatric lung disease, pediatric thromboembolic disease, pediatric hypobaric hypoxic exposure,
and the last one, pediatric pulmonary vascular disease associated with other systemic disorders. So as you can see, this gets much closer to
really adequately classifying pediatric pulmonary vascular disorders. And I think it’s important
for many reasons in terms of characterizing the pathobiology of these disorders and going
on to clinical trials. You really want to try to separate the different types of pulmonary
vascular disease. So Jeff, that’s a very helpful overview as
to where we are in that new classification scheme. But could I press you on that a little
bit? We often hear about these expert consensus groups and come up with a new classification
scheme. And candidly, what is the importance of that? Is this going to change in two or
three years? Where does that take us? Why is this scheme important? Well, I think it will continue to be modified
and improved upon. But I think it’s important one, to just collect the epidemiologic data,
which is a moving target and evolving. Because as I alluded to earlier, I think we’re starting
to appreciate more and more vascular disease associated with other disease states, which
we hadn’t really appreciated well before, bronchopulmonary dysplasia being an excellent
example of that. So one, just to understand the epidemiology
of the pediatric disease is important. I think the classification helps with that. And then
hopefully as we go on to clinical trials, I think it’ll be important to randomize or
study patients within groups to see if different therapies can help different groups. We’d like to turn now and ask our colleagues
around the world a question. Could you first write your city and country that you’re located
in? And the question is this. Utilizing the framework and classification scheme that Dr.
Fineman has just presented here, could you list the top three causes of pulmonary hypertension
in your pediatric population? We’re back now with Dr. Jeff Fineman. Jeff,
the next question becomes moving into treatment. We’re past classification. How do you think
about organizing your team in San Francisco to approach a comprehensive treatment plan
in these patients? Well, I think it’s very important that we
have a team that’s multi-disciplinary. As you know, pulmonary, pediatric pulmonary vascular
disease reaches across a broad spectrum of subspecialties. And various subspecialties
specialists will see these patients, whether they realize it or not. And I think the best
way to do it is with a collaborative, multi-disciplinary team. Certainly a cardiologist is paramount to this
group. And having someone who does cardiac catheterization is very, very important and
be able to do interventions. We also have a pulmonologist who helps us particularly
with the patients with lung disease. And we have a neonatologist who helps us with many
of the neonatal disorders and the lung hypoplasia disorders, the congenital diaphragmatic hernias,
for example. I’m an ICU doctor, so I tend to focus on more
of the inpatient management, particularly the acute inpatient management. And then as
you know, there are complex patients. And they require a lot of care. And they have
a disease that often is a chronic disease with no real cure in sight. So having social
work support, great nursing support. I think also as part of the team, you need
to have collaborative pediatric surgeons and ultimately transplant surgeons, cardiothoracic
surgeons. And then you have to have your other subspecialists that may run into these patients
like the hematologists, for example, the rheumatologists, for example. I think that they need to be
educated and be part of the group. And so they’ll send patients for screening when appropriate. Then as you know this is not only a complex
disease, but it can be a devastating chronic disease with not– although our therapies
have certainly improved survival, there’s no real cure in sight. And so there needs
to be a lot of support systems for these patients. And we like to set up the clinic where we
have a social worker, a nutritionist, a pharmacist that are all focused on these particular patients. And the clinic is within our cardiopulmonary
clinic. So we really try to organize it so they’ll have one visit, and the subspecialists
go to them. We’d like to turn now and ask our colleagues
around the world a question. Could you first state your city and country location? And
the question is, in your program, are patients with pulmonary hypertension managed by a pulmonary
hypertension service or team, or are they managed by an individual specialist? If an
individual specialist, which specialty typically manages those patients at your center? So Jeff, one of the questions that often arises
is how would you characterize the most significant advances in treatment over the last 25 years?
What were the key breakthroughs and what steps? Well, I think from a pathobiological standpoint,
our understanding of endothelial pathology as being a significant contributor to the
disease has led to many endothelial based therapies. And I think that’s really been
the most exciting component of the field. And if you look at a timeline of FDA approved
medications, and unfortunately I’m talking about adult approved medications, there’s
really been a substantial increase in the number of different medications that have
been approved to treat pulmonary vascular disease. Having said that, I think that we are really
barbaric in the way we approach the therapy to this disease in the sense that it’s clearly
a spectrum of disease with multiple etiology and probably multiple pathobiological cascades
being affected. And right now it’s, I’d say it’s similar to an analogy of maybe 30 or
40 years ago when a patient had cancer, you would say, you have cancer. And we have five
drugs. And we’ll give you one. Or we may add a second. Or we may add a third, without really
understanding the biology of that particular cancer and then targeting the therapy. And obviously our oncology colleagues have
done a spectacular job of characterizing the different cancers in the targeted therapies.
I think that’s where we are back there in the pulmonary hypertension therapeutic realm
in the sense that we have certain therapeutic targets, but we utilize them all for all the
patients. And we just don’t understand enough about the pathobiology of each different disease
within a particular patient. And we don’t have markers to try to even start to characterize
that. And so we cannot target our therapies. Having said that, it’s really been very exciting
in terms of the additional therapies that we have that have clearly changed this disease.
I mean, the overall survival is much, much better than it was 10 years ago. And our ability
to treat them with transitions from intravenous to subcutaneous where you don’t need an indwelling
catheter and the risks of infection or thrombosis, and now oral agents that are coming along
that really are improving the lifestyle of our patients. The next slide shows a timeline of the different
therapies that have been approved by the US Food and Drug Administration for pulmonary
vascular disease. As you can see, in 1995, all we really had was calcium channel blockers,
anticoagulants, digoxin, and diuretics. And we still use some of those today. And 1995
was really the first drug, epoprostenol, or Flolan, that was approved for pulmonary hypertension.
And as you know, it’s a prostacyclin as seen in grain. And it had to be given continuously
intravenously. Then there’s a gap of six years until we got
a new class of drugs, the endothelin receptor antagonists, with Bosentan being the first
one. Treprostinil, which is another prostanoid, but has a longer half life than Flolan and
is given subcutaneously, and it’s also stable at room temperature. So this made the delivery
of prostanoids much simpler. In 2002, it was approved. And in 2004, the IV formulation was approved,
as well as the inhaled prostanoid, Iloprost. Sildenafil, which again is the third classification
of drug, a phosphodiesterase five inhibitor was approved in 2005. Then there have been
some additional endothelian receptor antagonists with Ambrisentan in 2007. And then more recently
in 2013, Macitentan was approved. But then inhaled Treprostinil or Tyvaso was
approved, which is a longer acting inhaled prostanoid formulation. And then Tadalafil,
a longer acting phosphodiesterase five medication. And then lastly in 2013, in addition to the
new endothelin receptor antagonist, we have Riociguat, which is a soluble guanylate cyclase
activator, a new or a fourth class of drug. And then a very exciting drug, an oral Treprostinil,
or oral Remodulin, which is an oral prostanoid. And that could replace, if shown to be as
efficacious, the subcutaneous or intravenous route of prostanoid administration. Jeff, that’s a wonderful overview of some
of the most significant breakthroughs, at least as licensed by the FDA for adults as
you noted. In pediatrics, I well remember the early ’90s when nitric oxide was being
used in an investigational sense. Could you take us through the story of nitric oxide,
in particular, nitric oxide in our field of pediatrics? Sure, and nitric oxide, as you know, is the
only approved therapy for children. It’s approved for neonates with hypoxemic respiratory failure.
That whole other side of therapies is just approved for adults. So the nitric oxide story
is one that’s near and dear to our hearts. Because it’s so rare for a medication to group
approved primarily for a pediatric, let alone a neonatal, indication. The whole nitric oxide story is extremely
interesting and exciting. Because as you know, it was a molecule that was found to be produced
endogenously by the vessels, by the endothelial cells. And not only is it just a therapy,
but it’s clearly aberrations in the nitric oxide system are perturbed in pulmonary vascular
disease. So it can almost be considered like a replacement therapy. Throughout the years, our approach to lowering
the pulmonary vascular resistance was always to try to dilate the pulmonary vasculature.
And oxygen was really the only one that we could utilize that dilated the pulmonary vasculature
without diluting the systemic vasculature and resulting in systemic hypotension. And
we used, as you know, many, many drugs that dilated both the pulmonary vasculature, but
they were always limited by the systemic hypotension that they created. So there was always this search for the panacea,
the selective pulmonary vasodilator. And really, nitric oxide filled that bill to some extent.
The nitric oxide, the gas, has been around for a long time. And you could find it in
any anesthesia gas catalogue. It’s in a tank. And it has been used for many decades in diffusion
capacity studies. And as you know, anesthesiologists in this town thought about the concept of
delivering it as its natural gas inhalationally as a selective, potentially selective vasodilator.
Because once it hits the bloodstream, it avidly binds with hemoglobin and then is inactivated. You’re referring to the early work of Warren
Zapol at the Massachusetts General Hospital. That’s correct. That’s correct. Now, there
was always the concern of nitrogen dioxide, which is clearly toxic to the lungs. And so
if nitric oxide sat around or was exposed to oxygen, it would avoidably form nitrogen
dioxide. So I think the work was held up by this fear of pulmonary toxicity. But it was
related to nitrogen dioxide, as opposed to the pure nitric oxide gas. And they showed initially in animal studies
that it actually produces very potent pulmonary vasodilation and is selective. And then in
modest doses, it was safe. And then as you know, people at Boston Children’s Hospital,
David Wessel, studied it predominately in the congenital heart disease population for
postoperative pulmonary hypertension. And they showed very nicely that it was a very
potent and selective pulmonary vasodilator and has really become our mainstay of acute
pulmonary hypertensive therapies in the ICU setting. The neonatologists got together. And there
were several studies, multi-centered studies, that were done. And they showed not only safety
but efficacy in about a 30% reduction in the need for extracorporeal life support in neonates
with hypoxemic respiratory failure. And it was for that indication that the Food and
Drug Administration approved inhaled nitric oxide. Jeff, can I ask you a question about nitric
oxide therapy outside of that category of the newborn? At our center, it’s often the
case that you have an older child who may have ARDS and is approaching terminal hypoxemia.
And not infrequently, the clinicians will often in the middle the night add in nitric
oxide. And sure enough, there will be a transient benefit in the A-a gradient, undoubtedly because
of the V/Q matching. But when the team comes back in the morning,
typically the more senior staff will say, “The saturations went up, but the studies
clearly show it doesn’t work in this case.” Are there individual cases where you use it
as a rescue therapy despite the fact that all of the controlled studies in adults and
children haven’t demonstrated a significant long term improvement in outcomes? Are there
individual cases where you use it as a rescue therapy for terminal hypoxemia? That’s an excellent question. So as you know,
there are two primary effects related to its vasodilation, that you can lower pulmonary
arterial pressure and vascular resistance, and therefore unload the right ventricle.
But you can also improve ventilation perfusion mismatch and get improvement in oxygenation,
as you point out. And the studies have really been very consistent that the improvement
is quite transient. And by 24 hours, it’s gone, which is interesting. And the mechanisms
of that are unclear. I would argue that in subsets of patients
where pulmonary hypertension associated with a lung injury is significant, such that the
right ventricle is struggling, that in that case, using nitric oxide in doses that promote
significant pulmonary vasodilation could potentially help individual patients. So although those
studies don’t select for the patients that have associated pulmonary hypertension related
to the lung injury, I would argue that that would be a study that’s worth doing, where
you take a population of patients where there is significant pulmonary hypertension associated
with their acute lung injury and see if it helps them. So in answer to your question,
I do use it in subsets of patients, particularly where we think either clinically or echocardiographically,
the right heart may be struggling and that there’s elevated pulmonary arterial pressure. Can I push you a little more? Do you routinely
use transthoracic echo to first demonstrate that you have right ventricular dysfunction
and clear evidence of right ventricular failure in the setting of pulmonary hypertension and
then look at it again to see if there’s a dose response? Or are you willing to sometimes
do it, as you suggested as well, just based on clinical impression? Generally what I do is I would get a B-type
natriuretic peptide level, plasma level, and see if it’s elevated. Because if it’s normal,
I think the chances of there being any right ventricular dysfunction are minimal. If it’s
elevated, then I’d ask my cardiology colleagues to do a transthoracic echo. And if there’s
evidence of elevated pulmonary arterial pressure, then I would utilize nitric oxide. Interesting. Well, that leads I think to the
next question that I don’t doubt that many colleagues are wondering. And I’m wondering
myself. When you’re in the ICU in San Francisco and you face a patient with an acute pulmonary
hypertensive crisis, take us through the escalation of therapy that you’re thinking about. What
are you starting first? What are you going to add on? What are the adjunct therapies?
When are you going to consider diagnostic tests such as a cath? When would you not consider
a cath for fear that that could be a precipitating event? Could you take us through your therapy? Sure. I think the first important issue is,
in terms of the approach, is the recognition that this is a pulmonary hypertensive crisis.
And that may or may not be obvious. So as you know, some children with pulmonary hypertensive
crises, they can develop very severe bronchoconstriction, whether it’s related to proximal compression
of the airways from an acutely dilated pulmonary artery or distal bronchoconstriction, or both. But you can be called to the bedside. And
the patient’s chest, assuming they were on the ventilator, is not moving. So the assessment
then, as you know, is, is the tube out? Is the tube plugged? Or is this a pulmonary hypertensive
crisis? And that can be a very challenging assessment at the bedside. And you want to
be right. Because if it’s a pulmonary hypertensive crisis,
you really don’t want to waste time dealing with an airway that’s actually fine. But you
really have to try to make that assessment. So knowing the patient, knowing the history,
knowing the risk of them developing acute pulmonary hypertensive crisis, is important
when you get to the bedside. In terms of recognition I think it’s important that we understand
the pathophysiology of an acute pulmonary hypertensive crisis. And I think that’s well-delineated in this
next slide. So as you can see, there’s some inciting event. And in the ICU setting, it’s
often hypoxia, acidosis, or agitation. And those inciting events result in an increase
in pulmonary arterial pressure, an increase in pulmonary vascular resistance. And as we
know, patients with significant pulmonary vascular disease can have an exaggerated vasoconstricting
response to these stimuli. So you get a massive increase in resistance. And what makes it a pulmonary hypertensive
crisis is that the right ventricle fails. So the right ventricle will fail and dilate.
And you end up with an increasing right ventricular and diastolic pressure and volume. And this
by itself can result in ischemia and related dysrhythmias. Importantly, it can cause septal
shift, and a decrease in left ventricular end diastolic volume, a decrease in cardiac
output, and metabolic acidosis, which can further aggravate the pulmonary vasoconstriction.
That, as you can see, can be manifested in systemic hypotension. On the pulmonary side, you can have a significant
acute decrease in pulmonary blood flow and associated both small and large airway obstruction,
which leads to this rigid chest that’s so difficult to sort out when you come to the
bedside. This results in increased dead space ventilation and increased V/Q mismatching,
both resulting in hypoxia and respiratory acidosis. And that too feeds the fire, so
to speak, in terms of increasing the pulmonary vascular resistance. So this cascade needs to be broken by an acute,
thoughtful intervention. So if your assessment is that it is, in fact, an acute pulmonary
hypertensive crisis, you want to hand ventilate with 100% oxygen. And if you have nitric oxide
readily available at your center, then you want to blend that in to the circuit and just
hang in there. And as you break the cycle, then the chest will start to rise. And you’re in the midst of what you think
is a pulmonary hypertensive crisis. Are you going to put this patient on 80 parts per
million of nitric oxide, 20 parts per million? Where are you starting? I would generally start at 40 parts per million.
I think there’s animal data suggesting that the maximum was 80, as you know, but the instance
of methemoglobinemia is significant at that dose. So that’s no longer used. There’s not
a great deal of human data to guide us here. But in general, I think you can potentially
get more from 40 parts per million than 20 parts per million. But I wouldn’t go beyond
that. So I think 40 parts per million is a reasonably safe dose. And then once there’s
a response, I rarely stay on 40 parts per million. I’ll generally get down to 20 parts
per million rather quickly. And if you’re making progress, are using end
tidal CO2 amplitude to see improvement in pulmonary flow? What’s guiding you at the
bedside breath to breath and beat to beat? I think end tidal CO2 is helpful. I think
that the feel of the chest rising is helpful. As the compliance improves, your circulation
is probably improving. Obviously, saturation is helpful. And then because what you’re dealing
with is not just an elevation in pulmonary arterial pressure, but what makes it an acute
pulmonary hypertensive crisis is that the RV is acutely failing, impinging upon the
LV and impeding your output. You will start to see as the RV gets better, the LV output
improves. So that’ll be reflected in an increase in your systemic arterial pressure. And so you may or may not be making improvement.
Let’s say that it doesn’t appear that you are. Patients may be not deteriorating further,
but you’re clearly not moving out of this. You’re concerned that the RV is still under
stress. What are you adding next? What are doing next? I think it’s hard to add a lot of things beyond
pulmonary vasodilator therapy in the very acute setting. But if you’ve broken this spell,
and again you want to give 100% oxygen. You want to make them alkalotic. So that can most
quickly be accomplished with hyperventilation and achieving hypocarbia. But you can also
give bicarbonate to help you with that. And then inhaled nitric oxide. Once you’ve broken
that spell, I think then you can reassess and not only add some more pulmonary vasodilator
therapy, but also give agents to try to support both the right and the left heart, depending
on the particular circumstances. Can I press you? What’s the harm of saying,
I want to add an inotrope now? I’m concerned this RV is really in fulminant failure. And
now’s the time to add in an inotrope. Any harm in that? Low dose epinephrine, dopamine
at 10 mcg per kilo per minute? Certainly there is now a role for considering
the use of vasoactive or inotropic support. First, let’s not forget about optimizing preload
in this situation to the right ventricle, which as you know, in the acute situation
may involve volume loading. But often in the subacute or chronic situation, it involves
diuresis of the right ventricle. CVP monitoring can be extremely helpful in this situation
to guide your volume management. And as I should have brought up when were
talking about acute pulmonary hypertensive crises, CVP monitoring or monitoring right
atrial pressure can be extremely helpful in one, identifying a pulmonary hypertensive
crisis, where you’d expect the right atrial pressure to be elevated, and also to guide
your therapy, where you would expect right atrial pressure to be decreasing as your pulmonary
hypertensive crisis is being broken. In terms of inotropes, you know that there
are several options. And decisions are often made based on their effect on cardiac output,
as well as their effect on the peripheral vasculature, both the pulmonary and the systemic
vasculature. As you can see, there’s data on the effects of several agents on cardiac
output and vascular resistance. But please keep in mind when they’re talking about the
inotropic effects of these drugs, oftentimes these things have been studied on the left
ventricular contractility as opposed to the right ventricular contractility. Also keep in mind that in terms of the vasodilating
or vasoconstricting effects of the vasculature, that the effect of a particular agent may
be influenced by a variety of factors. Because the receptors that they activate are either
up regulated or down regulated by a variety of factors, including how long they’ve been
on these medications, the presence or absence of sepsis, their nutritional status, et cetera.
So the bottom line is, you start one of these medications on a particular patient. And you
must observe closely to see what the particular effects are on your patient. You should also realize that the effect of
these vasoactive active agents on the peripheral vasculature is often tone dependent. In other
words, if the vasculature is in a very dilated state, the chances that one of these agents
will further dilate it is minimal. But some general principles when selecting an inotropic
agent are one, avoid agents that would increase pulmonary vascular resistance in this situation.
Although you can argue that concomitant use of selected pulmonary vasodilators like inhaled
nitric oxide and 100% oxygen would likely offset the pulmonary vasoconstricting effects
of most agents. You should certainly avoid tachycardia. Because
tachycardia can certainly hurt your right ventricular output and increase myocardial
oxygen consumption of the RV. And avoid systemic vasodilation if possible, particularly in
the setting of a dilated right ventricle. Because as you know, that can really negatively
impact RV-LV interactions. And so, Jeff, you’ve stabilized the patient
as you’ve described with 100% oxygen, nitric oxide through hand ventilation, alkali therapy.
And yet the patient is still having episodes three, four, five hours later. We’ve all had
these patients, where you’ve stabilized initially, but now episodes of acute desaturation associated
with systolic hypotension. You’re obviously still brittle. The RV is still under severe
strain. RV dysfunction is still a concern. What are therapies, three, four, and five
in your armamentarium? So this is somewhat of a stylistic choice.
But before I give you the treatment options, I would say that you must always think about,
is there something that we’re missing? So if the cause of the pulmonary hypertension
is clear, for example, it’s a VSD that was operated on a little bit older and is now
in the perioperative period, where it’s very clear what’s going on. Then I don’t think
further diagnostic evaluation is necessary. But depending on the situation, you should
always think about, is there something that’s missing, that we’re missing that could be
contributing that we need to know about? And so the potential for diagnostic evaluation
should always be thought about. Having said that, in the acute setting, I think in terms
of adding pulmonary vasodilator therapy in an intubated, mechanically ventilated patient,
I think utilizing Iloprost in addition to the nitric oxide is a nice touch. It’s selective, again, so you don’t have to
worry about the systemic hypotension. And as we alluded to with the left ventricle,
if anything, we want the systemic vascular resistance to be a bit on the high side to
help the right ventricle, left ventricular interdependence. And it works via cyclic AMP
activation, where inhaled nitric oxide works via cyclic GMP activation. So at least theoretically, there may be some
additive effect, where one patient– if one cascade may be perturbed more than the other
in a particular patient, you may see one benefit more than the other. So I like to add Iloprost.
And it can be nebulized into the airway through the ventilator. It has to be given quite frequently.
But you’re in the ICU, so it’s not as big an issue. So I would add, acutely, in addition
to nitric oxide, I’d add Iloprost therapy. And then I would give something to support
the heart. I generally give Milrinone as an inotropic and lusitropic agent. Then again
though, depending on how dilated the right ventricle is, we may also add a vasoconstrictor
like Vasopressin to support systemic vascular resistance. Since some of the cardiac output
problem is the fact that the RV is dilated and impinging upon the LV and that the output
of the RV is somewhat LV-dependent as you know, that if you can utilize a vasoconstrictor
like norepinephrine. We like to use Vasopressin because it doesn’t have any pulmonary vasoconstricting
effects, just systemic. If you tighten up systemic vascular resistance,
you could potentially get that LV to be a little bit bigger and improve the ventricular
interactions, and thereby improve output. Obviously, your LV has to be a good functioning
LV when the right ventricle is not impinging upon it. But if inherently there’s no disease
in the left ventricle, then it can be a very helpful therapeutic modality when you’re really
struggling with severe RV dysfunction that’s impinging on the left ventricle. And then obviously diuresis can help out subacutely
for the right ventricle. But when you talk about inotropes for the right ventricle, you
bring up a very important area. I think investigation and therapeutic targeting for pulmonary hypertension
over the last couple decades, which has been terrific, has appropriately focused on the
pulmonary vasculature and the potential endothelial injury and mechanisms of the smooth muscle
remodeling. And because of that work, there are several new drugs and many new drugs which
target the vascular proliferation that are down the pike and I think will come to human
trials soon. And that’s very exciting. However, as you know, ultimately this becomes
a disease of right heart dysfunction and failure. And in terms of long term survival for these
patients with the chronic forms of pulmonary hypertension, it’s really their right ventricular
dynamics that are the best predictors of outcome, as opposed to their pulmonary dynamics. In
other words, it’s not how high their pulmonary vascular resistance is, but indices of right
ventricular function including right atrial pressure are better predictors of long term
survival. So appropriately in parallel with these exciting
investigations of pulmonary vascular mechanisms of disease, there’s learning new insights
about the right ventricle. And we realize, similar to it’s hard to take an adult medication
and say it’s going to work in a child, it’s not appropriate to say a medication that works
for the left ventricle is going to work for the right ventricle. Because as you know,
they come from different developmental origins. Their muscle fiber orientation is very different.
And the mechanisms in which they contract are very different. So we utilize drugs that improve the inotropic
state of the heart. But we really don’t have drugs that work effectively for the right
ventricle. So understanding the mechanisms of adaptive and maladaptive right ventricles,
why some patients’ right ventricle seems to work much longer and better than others, whether
it’s a genetic predisposition, or what are the mechanisms of that adaptation, a really
interesting area of new investigation that I think will get us targeting therapies for
the right ventricle that may have a significant impact on these patients’ lives. Well, Dr. Jeff Fineman, thank you very much
for a wonderful overview of pulmonary hypertension and also for telling us how you approach these
problems in San Francisco. Thank you. What an honor to be here. Thanks
very much. Sure.