Why is PGE contraindicated in PPHN?

offlabel · May 2

Just spit balling here...prolly has to do with the potential of PDA in kids with PHTN. Keeping the ductus open with PGE will just increase aortic flow to the PA and make the PHTN worse?

Although this paper would contradict your question in the first place:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808469/

Especially this:

Prostaglandins: Two classes of prostaglandin have therapeutic applications for treatment of PPHN: prostacyclin (Prostaglandin I2, PGI2) and prostaglandin E1 (PGE1). Prostacyclin (PGI2) mediates vasodilation by activating adenylate cyclase and increasing cAMP in the pulmonary arterial smooth muscle cell (figure 1). In newborns, prostacyclin partly mediates pulmonary vasodilation at birth in response to ventilation of the lungs; it does not play a significant role in vasodilation in response to oxygenation 39,40,41. In a study of lambs with PPHN induced by antenatal ductal ligation, pulmonary prostacyclin synthase and PGI2 receptor protein levels in the lung were decreased, but the adenylate cyclase levels were not altered42.

PGI2 analogs are the mainstay of pulmonary vasodilator therapy in adults and children with pulmonary arterial hypertension (PAH), and the intravenous route is the most studied. All PGI2 analogs have the limitation of an extremely short half-life. Prostacyclins are currently approved in multiple forms and are listed below:

Epoprostenol (intravenous)

Treprostinil (oral, intravenous, subcutaneous)

Iloprost (intravenous, inhaled)

Beraprost (oral)

NICU_Nurse_Casti, BSN, RN · May 3

I cannot think of a reason not to use PGE for PPHN, other than maybe some left to right shunting through the PDA. But PPHN is due to increase PVR, so there should not be much, if any, left to right shunting through the PDA. PGE works as a vasodilator, and should help relieve some of that PVR, as well as keep the PDA open in case the PVR becomes much greater than the SVR and you get severe PPHN. PGE therapy an also cause apnea, which could increase PVR, but most PPHN babies I have managed were intubated, so not usually a major concern there. Hyperthermia could be another reason. I am not 100% sure. But Gomella's Neonatology does recommend the use of prostaglandin therapy as management for PPHN. It could be the information in your lecture is outdated?

NICU_Nurse_Casti, BSN, RN · May 4

NICU_Nurse_Casti said:

I cannot think of a reason not to use PGE for PPHN, other than maybe some left to right shunting through the PDA. But PPHN is due to increase PVR, so there should not be much, if any, left to right shunting through the PDA. PGE works as a vasodilator, and should help relieve some of that PVR, as well as keep the PDA open in case the PVR becomes much greater than the SVR and you get severe PPHN. PGE therapy an also cause apnea, which could increase PVR, but most PPHN babies I have managed were intubated, so not usually a major concern there. Hyperthermia could be another reason. I am not 100% sure. But Gomella's Neonatology does recommend the use of prostaglandin therapy as management for PPHN. It could be the information in your lecture is outdated?

Not sure who gave me a down vote, but if you see this and care to explain, I'd love to know. I'm always trying to learn, so it would be helpful to have some constructive feedback. Thanks.

chare · May 4

NICU_Nurse_Casti said:

Not sure who gave me a down vote, but if you see this and care to explain, I'd love to know. ...

My apologies.

NICU_Nurse_Casti, BSN, RN · May 4

chare said:

My apologies.

No worries! I was just curious. 🙂

adventure_rn, MSN, NP · May 9

I'm a peds cardiac NP with a background as a NICU nurse, so I can take a stab at answering this one. It's actually a really interesting question. Breaking it down into more manageable questions:

1) Why do we generally not use PGE?

In a normal newborn, the PDA is supposed to close during transition as a) pulmonary venous pressure drops, and b) circulating prostaglandin levels (produced by the placenta) decrease in the baby's blood. Conversely, two main things tend to keep the PDA open after birth, either a) pulmonary venous pressure remains high (I.e. PPHN) and stents the PDA open, or b) you give exogenous prostaglandin (PGE) to intentionally keep the PDA open (I.e. for kids with ductal-dependent cardiac lesions).

PGE isn't a mainstay therapy in PPHN because it isn't a particularly helpful treatment. It's a vasodilator, but it's not a particularly good one, and it has a lot of harmful side effects. In PPHN, the goal is to lower pulmonary pressures/PVR while maintaining systemic blood pressures/SVR. The reason inhaled nitric oxide and oxygen are the mainstays of therapy are because they are selective pulmonary vasodilators. In general, we don't give systemic vasodilators to a kid with PPHN in an attempt to lower their PVR, since we don't want to bottom out their systemic pressures. Rather, you only want to lower their pulmonary pressures relative to their systemic ones.

At the same time, the only body part that PGE is particularly 'selective' for is keeping the PDA wide open, and a wide open PDA is actually going to increase your pre- and post-ductal O2 sat gradient. In PPHN, you have high pulmonary/right heart pressures (deoxygenated blood) and low systemic/left heart pressures (oxygenated blood). In severe PPHN where kids have a pre- and post-ductal sat gradient, they are only shunting right to left. The high PVR forces the deoxygenated blood across the PDA, and prevents it from closing. Pre-ductal (right hand) blood only reflects the oxygenated blood coming from the left heart, while post-ductal blood is a mixture of the oxygenated blood from the left and a ton of deoxygenated blood from the right shunted across the PDA.

Of note, kids with bad PPHN don't have PPHN because of their PDA, they have a PDA because of their PPHN, since the high pulmonary pressures are stenting the PDA open. Therefore, giving a PPHN kid PGE isn't going to make their PPHN worse. However, keeping the PDA open even wider can make their pre- and post-ductal sat differential even greater. If you have a smaller PDA, there will be more resistance to the blood shunting right to left, and the less right to left shunting you have the smaller your pre-/post-ductal gradient will be.

So to answer your first question: We don't give PGE to kids with PPHN because a) it won't really help (and has a bunch of side effects), and b) it will keep their PDA open wider, which could more right to left shunting, worsening their pre-/post-ductal gradient.

That said, there is some new research about severe cases (like CDH) where we should use PGE, which is probably what your presentation is referring to:

2. Why might we use PGE in severe cases?

The purpose of giving PGE to kids with extremely severe PPHN is to prevent right-sided heart failure and circulatory collapse. In a normal patient, blood leaves the right heart and goes via the pulmonary artery (PA) out to the lungs. In a baby with PPHN and a huge PDA, the blood leaves the right heart and has two options: it can either a) keep going (against high PVR) out to the lungs to pick up oxygen, or b) choose the path of least resistance and get shunted across the PDA out to the body. The blood going out to the body will be deoxygenated (blue), but you're still getting perfusion to your body and maintaining a blood pressure.

Conversely, imagine a baby with severe PPHN and NO PDA: The blood would come out of the right heart and then just...get stuck. The pressure would be too high in the lungs for it to move forward, so instead it would just back up, and up, and up into the right ventricle, then right atrium, then the venous system. This is extremely dangerous for two reasons. First, your right heart is going to fail almost immediately. Second, if the blood getting is getting stuck at your lungs, then it can't move forward to your left heart, and then out to your body. With no forward blood flow, you have no cardiac output: no blood pressure, no end-organ perfusion (I.e. your brain), and no coronary perfusion (bradys and cardiac ischemia).

The idea behind giving these severe PPHN kids PGE is that it's better to have a very blue baby with a whopping PDA and a right-to-left shunt with a huge pre-/post-ductal gradient than a baby with no blood pressure at all. Babies can survive being pretty hypoxic--fetuses in utero have O2 sats around 60-70% (hence the NRP targeted oxygen guidelines), and cardiac babies can live for months at around 60-70% sats. However, babies can't tolerate huge swings in their perfusion/blood pressure, which is a big cause of germinal matrix bleeds/IVH, watershed injuries in HIE, and NEC.

For these kids, PGE helps to maintain the PDA as a 'pop-off valve' for the high pressure in the pulmonary arteries: instead of just getting stuck at the lungs, the blood can escape across the PDA over to the aorta, where it can go on to the body to maintain blood pressure and perfuse the other organs (albeit with low oxygen sats). Of note, the PFO is doing effectively the exact same thing inside of the heart. These kids will have a big right-to-left shunt at the level of the PFO: blood that gets stuck and the lungs and backed up into the right heart can escape across the PFO to the left heart, where it can perfuse the coronaries and go out to perfuse the body via the aorta.

In the moment, maintaining the PDA (via PGE) can prevent circulatory collapse. Over time, it's also going to help prevent right heart failure, which is extremely difficult to treat. The right ventricle is very stiff and bad at compensating. Even when kids with PPHN survive, if their right ventricle is irreparably damaged as a result of their PPHN episode and they end up in chronic right heart failure, they're at high risk for sudden death. The presence of the PDA (via PGE) is going to offload the pressure backing up into the right heart by creating a pop-off valve to the aorta and the rest of the body, so at the time of the PPHN episode they're less likely to experience right heart failure.

So to answer the second question: PGE might be used in severe cases because a hypoxic baby is better than one with no blood pressure (or as one of my attendings told me very bluntly, a blue baby is better than a dead one), and we also want to avoid right heart failure at all costs.

Here are a couple of recent articles studying how PGE can be used in these severe cases. The primary outcome measures (BNP, tricuspid regurg, right ventricular systolic function, right ventricular afterload, lactic acidosis) show that that it improves right heart failure. The secondary outcomes (lack of systemic hypotension, no worsening in post-ductal hypoxemia) suggest that the addition of PGE doesn't cause any further harm.

https://pubmed.ncbi.nlm.nih.gov/30442461/

https://pubmed.ncbi.nlm.nih.gov/37975485/

So to answer your question overall: in kids with mild to moderate PPHN where blood is still able to make through the lungs, PGE isn't necessarily very helpful (and it always comes with risks like apnea and hypotension). However, in kids with PPHN so severe that they are at risk of circulatory collapse or right heart failure (I.e. a huge CDH), it can prevent further harm.

Thanks for posing the question!! It was super interesting reasoning through why we do/don't use PGE in PPHN, and I learned a lot from reading the articles!

adventure_rn, MSN, NP · May 9

Since you're working on a full congenital cardiac lecture, might I refer you to another NICU cardiac discussion we had on this forum a couple of years ago:

https://allnurses.com/lower-o-sat-parameters-babies-t712962/

If you have any NICU cards answers I'm happy to answer them to the best of my ability, it's my favorite topic.