At this point your head is likely spinning when it comes to managing the PDA. Should we treat it early, late or not at all? My last post was about benign neglect which may be well and good for the unit you work in but if you believe that these ducts can cause problems and want to treat them then you can choose from indomethacin, ibuprofen or paracetamol. Paracetamol (tylenol as you may know it better) is an old dog that has learned some new tricks. The former two drugs can be harder on the kidneys so with some recent data suggesting paracetamol may be equally effective to the other two, interest has grown. I had trouble at first understanding how this drug could help close a PDA since the other two I knew were effective through their anti-prostaglandin activity. It turns out that paracetamol is as well but just through a different mechanism. Paracetamol’s effect is likely through inhibition of the second active site on the prostaglandin H2 synthase, the peroxidase (POX) component.
Oral or IV
If you asked most people which route would be more effective the guess would be IV. Oral meds take time to be absorbed so wouldn’t you want a drug that goes straight to the target tissue as quickly as possible? The answer at least from what we learned with ibuprofen was no. There is in fact a cochrane review on the subject entitled Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. The conclusion favoured oral dosing and the reason for the greater benefit it turns out has to do with that slow absorption I talked about. While the IV dose will get the drug going where it needs to go faster and give you a quicker peak, the slow absorption of the drug gives you a longer time with a drug level above the blood level required to have the desired effect on ductal closure. In other words, slow and steady wins the race. It’s not surprising then that as knowledge and use of paracetamol spreads that similar questions would arise. This in fact led to a retrospective study looking at this exact question. Gover et al published Oral versus intravenous paracetamol for patent ductus arteriosus closure in preterm infants. which sought to examine the difference in the two routes of administration for 50 infants in their unit that received the drug for closure of a hemodynamically significant PDA. They excluded any infants who had received treatment for a PDA previously or paracetamol for pain relief so that they could really restrict the exposure to just closure of the PDA. They defined hemodynamically significant as a “moderate to large PDA, coupled with evidence of shunt burden, myocardial compromise, and continued need for significant respiratory support.” The drug was given from 3-7 days and was at the discretion of the Neonatologist. Longer courses were given for PDAs that were still open at 3 days and dosing was otherwise the same.
What Did They Find?
In terms of effectiveness the following figure maps out what happened with both oral and IV routes. For the whole 50 patients, 56% achieved closure after one course. Although the numbers are of course small, if you look at the oral group 15/19 or 79% had closure after one course vs 8/20 or 40% with IV alone. That’s quite a difference although again numbers are small here so we have to be careful about jumping to too big a conclusion (although it is in the direction we might have expected from the ibuprofen data). As this was not a randomized study it is difficult to know for certain that other factors were not at play here to explain the difference in closure rates but the authors did attempt to adjust for that and still found a benefit to oral administration.
Could this be explained by a difference in paracetamol levels in the blood? This is what I wondered about earlier in this post so maybe there is something to that? The authors looked at this as well by searching for a difference in trough levels prior to the 5th dose (no different). While it is tempting to write this off as a possibility then it is worth noting this is just one level in time. This was not a prospective, randomized study where serial levels could be taken to establish a pharmacokinetic patterns for the levels. While the one level is not different based on route I can’t help but wonder if these results are indeed real could the levels be above the minimum threshold for ductal closure longer.
An RCT will be needed to look at determining an answer here for sure but this is a great start no doubt. One thing that I can’t help but wonder about in this retrospective study is the “why” each Neonatologist chose oral vs IV. My guess is that in most cases the sicker the baby the more likely they were to receive IV. Babies who were quite sick on vasopressors or had demonstrated poor gut perfusion on ultrasound may have been more likely to get the IV form. These same patients are expected to have greater degrees of systemic inflammation and that is not good for ductal closure. Is the worse effect of IV therapy related to the drug itself or is it related to the overall state of the baby making closure less likely in the presence of inflammation?
I look forward to seeing a prospective study on this but maybe when possible for the time being it wouldn’t hurt when possible to give paracetamol orally? Interesting story that we will hear more about!