“Master Teacher Series: Case Study on Inhaled Nitric Oxide” with Dr. Wessel for OPENPediatrics

“Master Teacher Series: Case Study on Inhaled Nitric Oxide” with Dr. Wessel for OPENPediatrics

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Thank you for joining us. This short video
is part of a Master Teacher Series and features Dr. David Wessel. In the following video,
he will discuss clinical insights related to the use of nitric oxide. David, as you know, our colleagues Jeff Fineman
and Steve Schwartz, in prior World Shared Practice Forums, have spoken to us a great
deal about pulmonary hypertension and evidence-based literature to guide treatments of the patient
with pulmonary hypertension. But you did really the foundational research on inhaled nitric
oxide in the pediatric patient with pulmonary hypertension. What special lessons should
we all know about inhaled nitric oxide in the pediatric patient? Well, I’ve seen both of those forum presentations
and they’re excellent. And so I’m not going to try to cover the principles that have been
outlined there. I think the therapies that were described and the treatment algorithms
are outstanding. I did want to point out a couple of hazards. We know that inhaled nitric oxide, because
it’s a selective vasodilator, in this patient population of children with heart disease
is enormously helpful. Although I do need to point out that it’s still not a drug that
has a labeled indication in children. Yes, in newborns with hypoxemic respiratory failure,
but there’s not a labeled indication. In large part because we haven’t been able
to come to agreement with the Food and Drug Administration on the endpoint. The Food and
Drug Administration feel strongly that we should have a randomized trial with no opportunity
to take a patient with pulmonary hypertension who has congenital heart disease who has been
treated with a placebo standard therapy and ever give them inhaled nitric oxide, even
as a rescue therapy, in that branch of the randomization. And frankly, the practitioners are reluctant
to randomize children who have pulmonary hypertension to therapy that prevents them from ever getting
inhaled nitric oxide. And so we have been able to do the studies. And the drug is not
labeled for use in children with heart disease beyond the newborn period. But having said that, we know as a selective
vasodilator it’s enormously useful, especially in the early postoperative period to attenuate
pulmonary hypertensive crisis. There are a couple of really important limitations of
the drugs I want to point out. Number one, in the newborn, especially the
asphyxiated newborn, where we as consultants may be called up to the newborn intensive
care unit for a patient they’re worried about having persistent pulmonary hypertension with
a newborn, where nitric oxide might be a good drug. We have to make sure that the echocardiogram
that is done, which typically shows shunting right-to-left across the PDA, is not because
the left ventricle is failing. So in an asphyxiated newborn, you may have
marked left ventricular dysfunction. That LVEDP rises. And that gives a kind of reflex
elevation pulmonary vascular resistance that feeds back on the right ventricle, which is
working well. And if the ductus is open, then that’s terrific.
Because the blood from the right ventricle, it’s blue, but it goes right-to-left across
the ductus and it supports the systemic circulation. So now that right ventricle is supporting
both the pulmonary blood flow and then the systemic circulation across the ductus arteriosus.
What happens if you take that patient with a failing left ventricle, give them nitric
oxide to breathe, and that pulmonary vascular resistance beautifully relaxes? And the right
ventricular output now goes to the lungs and not to the body. We have seen cardiovascular collapse almost
immediately after the initiation of inhaled nitric oxide in the patient with the right
ventricular dependent systemic circulation. So be very, very careful as cardiac consultants
that we point out that right-to-left ductile shunting. And yes. Systemic pressure in the
PA is not PPHN if the LV is not working. So that’s one point. There’s another point that I think merits
discussion in that patients with heart disease or those with cardiomyopathies that have big
dilated hearts, and left ventricular dysfunction, and high left atrial pressure. They’re often
tested with inhaled nitric oxide in the cath lab to see if they have reactive pulmonary
vasculature or are candidates for heart transplantation, that the PVR goes down enough to be a heart
transplant candidate. But if you leave nitric oxide on those patients for a prolonged time,
you’ll see that in many cases the pulmonary capillary wedge pressure actually rises. So you’ve unloaded that right ventricle. It
feels better. It tries to put more blood through the lungs. It fills and already completely
distended, dilated, and incapable left ventricle, incapable of doing more work and more filling.
And so the wedge pressure rises and they get pulmonary edema. So one has to be very careful about sustained
use of inhaled nitric oxide in the patient with a large dilated cardiomyopathy and pulmonary
wedge. We actually conducted a study some years ago,
not realizing this scenario and situation. But then during the study, we recognized that
some of the patients with elevated left atrial pressures, wedge pressures, were having trouble
even during the initial administration of nitric oxide with wedge pressures, pulmonary
edema. And there were two incidents of cardiac arrest. And we had to alter the study to eliminate
cardiomyopathy patients from the remainder of the study. So those are just two important
things to keep in mind. The final thing that I think everyone knows
now is that abrupt withdrawal of nitric oxide can contribute to a rebound or withdrawal
response. And that’s really how we got into the business of testing sildenafil for use
in pulmonary hypertension to prevent that withdrawal. But the sildenafil saga is a whole
other story for another time. Could I follow-up? What is your preferred
weaning strategy if an infant has been on inhaled nitric oxide for four or five days?
How quickly would you wean it down? I think the weaning protocols vary in different
units and different institutions. And I’m not sure we can say absolutely that there’s
one very best one. But I think over the course of typically three to four hours for a patient
who’s been on for a few days. One can wean from 20, to 10, to 5, to 1, and then off. But when you turn the nitric oxide off, I
think people need to be near the bedside, and be thinking about it, and watch the response.
If there’s an abrupt deterioration then you need to turn the nitric oxide back on and
try it more gingerly. Or you can consider giving sildenafil to attenuate the withdrawal
response. And that, of course, is in the context of a more sophisticated and comprehensive
view of what’s going on with this patient. We don’t know quite as much as we’d like about
the etiology of the rebound. Why it appears in some patients more than others. It does
seem to be a little bit related to the amount of time the patient gets the nitric oxide,
but not completely. And so there’s a lot more to investigate there.
A lot more to understand. And people like Jeff Fineman have a lot of insight into what
the mechanism there is in the withdrawal to inhaled nitric oxide response that we see. Thank you for viewing this case reflection
on the use of nitric oxide by Dr. David Wessel. If you would like to see additional case discussions
by Dr. Wessel, please view them on the OPENPediatrics website.

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