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.