As time goes by, I find myself gravitating to reviews of Canadian research more and more. We have a lot of great research happening in this country of ours and especially when I see an author or two I know personally I find it compelling to review such papers. Today is one of those days as the lead author for a paper is my colleague Dr. Louis here in Winnipeg. Let me put his mind at ease in case he reads this by saying that what follows is not a skewering of the paper he just published using Canadian Neonatal Network data (CNN). Over the last twenty years that I have had the privilege of working in the field of Neonatology we continue to discuss the same things when it comes to the PDA. Does it really cause problems or is it an association for many outcomes? Does treatment make a difference? If you treat then what should you use (ibuprofen, indomethacin, paracetamol)? When should you treat and if you treat early should it be in the first few days or right after birth using a prophylactic approach (provided within 12 hours of delivery)? It is the prophylactic approach which is the subject of this post!
Why treat prophylactically?
The TIPP trial reported the results in 2001 of the study whose goal was to determine if prophylactic indomethacin use could improve neurosensory impairment at 18 months by reducing rates of severe IVH. The results of the study are well known and showed that while the rates of severe IVH and PDA ligations were reduced through this approach, there was no actual effect on long term outcome. The use of this approach fell off after that for many years but recently resurfaced as some units in Canada opted to start the practice again as the two benefits seen above appeared to be worth using the approach. The thought from a family centred approach, was that eliminating the stress for families of informing them their tiny preterm infant had a serious intracranial bleed and potentially avoiding a surgical ligation with probably vocal cord impairment afterwards were good enough outcomes to warrant this practice. Having used this approach myself I have to admit one consequence is that indomethacin was so effective at closing the PDA most of the time that over time one begins to assume the PDA is in fact closed and is less likely to go hunting for one when the baby is misbehaving later on in their course. What if it didn’t close though? Are there any predictors that can increase our index of suspicion?
Answering the question
The CNN provides a large database to look retrospectively to answer such a question. In this article, the authors looked at a period from 2010 to 2015 including all infants < 28 weeks gestational age at birth yielding a very large sample of 7397 infants. Of these 843 or 12% received prophylactic indomethacin and from there a little over half (465) still had a PDA. From there, 367 received treatment with eventually 283 needing only medical, 11 having a PDA ligation and 73 having both medical and surgical closure. From this analysis so far I can tell you that providing prophylactic indomethacin certainly does not guarantee closure!
When a myriad of risk factors were put into logistic regression a number of interesting risk factors arose accounting for more of less risk of a PDA that needed surgical ligation despite prophylactic treatment. Much like all infants in the NICU, the risk for a persistent PDA was highest with declining GA. The combination of outborn status and short interval of ruptured membranes predicted higher risk. No doubt this is reflective of less frequent antenatal steroid use and even if provided time for it to work. Looking at medical or surgical treatment, surfactant therapy increased risk which may be explained by an improvement in oxygenation contributing to increased left to right shunting as PVR drops. Maternal hypertension and longer duration of rupture of membranes again play a role in reducing risk likely through the mechanism of the former increasing endogenous steroid production and the latter again allowing for steroids to be provided.
What can we learn from this paper?
I suppose the biggest benefit here is the realization that even with prophylactic indomethacin we are not assured of closure. In particular if there is a lack of antenatal steroid use or a stressed fetus one should be vigilant for the PDA. Interestingly, all of the risks seem to point towards antenatal steroid use. The bottom line then is that this reinforces what is already known and should be the focus of improvement strategies for centres. Increase the rate of antenatal steroid use and you will reduce the risk of a PDA even in the baby receives prophylactic indomethacin. I am happy to report that our centre has taken one step towards this goal by reinforcing to our Obstetrical colleagues that when they receive a call from a referring centre and have a woman who might be in labour it is better to err on the side of caution and just give the steroid course. If they are wrong on arrival then one can always repeat a course later on as we do although repeated courses of steroids are in and of themselves a contentious issue. What can your centre do to improve your results when it comes to antenatal steroid coverage?
There may be nothing that is harder in medicine. We are trained to respond to changes in patients condition with a response that more often than not suggests a new treatment or change in management. Sometimes the best thing for the patient is in fact to do nothing or at least resist a dramatic response to the issue in front of you. This may be the most common issue facing the new trainee who is undoubtedly biased towards doing something. Take for instance the situation in which the trainee who is new to the service finding out that their 26 week infant has a PDA. Their mind races as they digest this information from morning signover. There is less than 2 hours until they come face to face with their attending who no doubt will ask them the dreaded question. “What are you going to do about it?”. When having to choose a path, if they state “I want to sit tight and watch” they fear the thought of the attending thinking they don’t know what to do. Conversely they could stick their neck out and choose to treat with a variety of approaches but then might they be seen as too aggressive?! The likely path is suggesting treatment but in fact the more I think about it the option of benign neglect may be the best approach or at least one in which if you treat and it doesn’t work the first time you just shrug your shoulders and say “I’ll deal with it till it closes on it’s own”.
This post really is a follow-up to a previous one entitled The Pesky PDA. A Puzzle After All These Years. What triggered this writing was another before and after comparison of two periods in which the management of PDAs for a unit took a 180 degree turn.
Know When to Hold Em And No When to Fold Em
This is the essence of the issue for one unit. Sung SI et al published a paper this month entitled Mandatory Closure Versus Nonintervention for Patent Ductus Arteriosus in Very Preterm Infants. They describe a before and after comparison of 81 infants from 2009-11 and 97 infants from 2012-14. All babies were born between 23-26 weeks gestational age. In the first time period their unit had a mandatory PDA closure policy. That is they gave one course of indomethacin and if possible a second course followed by surgical ligation. A significant PDA was defined as one that had a left to right shunt and was at least 2 mm in diameter and the patient had to be ventilated. Any patient who had been extubated regardless of need for CPAP did not have to have their PDA closed. In the second time period the group attempted to avoid indomethacin and ligation at all costs and in fact in this cohort none received either.
So What Happened?
In the first time period 52 (64%) received indomethacin but only 29% responded and a full 37/52 (71%) went on to receive surgical ligation. Of the 29 that did not receive indomethacin due to contraindications they underwent primary ligation for a total of 82% receiving surgical ligation. The average day of closure for period 1 was 12.9 days.
In period 2 a number of interesting findings occurred. The average day of closure was at 44.2 days. Five infants were discharged with a PDA with 3 experiencing spontaneous closure after discharge and the remaining infants undergoing transcatheter occlusion. In period 2 there were more diuretics and fluid restriction employed. Comparing the two periods for a number of other outcomes reveals some other intriguing findings.
Even with such differing approaches there is no difference in mortality, severe IVH, ROP, PVL, NEC or sepsis. What is different though is the diagnosis of BPD yet there is no difference in total ventilation. In period 2 there is a shift towards more of this ventilation being HFOV less CPAP use at the same time.
What Might It All Mean?
It is retrospective and therefore we cannot be certain that there are not other variables that are not affecting the results that would have had a better chance of being evened out in an RCT. Having said that it is intriguing that having a PDA has been associated with BPD in the past but in this study having a PDA for a longer time is associated with a reduction in BPD. We know that longer periods of invasive mechanical ventilation increase the risk of developing BPD so it is intriguing that that there is no difference in mechanical ventilation yet there is more BPD when you are aggressive with the PDA. You might postulate that the need for surgery leads to greater need for ventilatory support and therefore damages the lungs but the needs for HFOV was higher in the second phase which at least hints that in terms of aggressiveness, Period 2 infants had a tougher go.
The culprit may be the heart. In period 1 there was a significantly increased rate of myocardial dysfunction and need for inotropes following ligation. It could well be that left ventricular dysfunction led to pulmonary edema such that in the 24-28 hours after the surgery ventilator requirements were increased and damaged the lung. The lack of a difference in overall ventilation days supports this possibility. Looking at the other common risk factors for BPD such as chorioamnionitis and lack of antenatal steroids these are no different between groups. Although not statistically significant there are more male infants in period 2 which would usually tip the scales towards worse outcome as well. It does need to be stressed as well that the rate of surgical ligation is higher than any study I have come across so the contribution of the surgery itself to the disparate outcome needs to be seriously considered.
What would I do?
Despite this study and some others that have preceded it I am not at the point of saying we shouldn’t treat at all. Our own approach is to give prophylactic indomethacin to such babies and then for the most part if a PDA remains treat one more time but at all costs try and avoid ligation. An RCT sounds like it is in the works though comparing the two approaches so that will certainly be interesting to see. It is tough to say what the future holds but to any young trainees who are reading this, the next time you are asked what to do about a PDA you are well within your rights to suggest “Maybe we should do nothing”!
Like many Neonatologists, I experience a complete body sigh when I discover that an ELBW infant has a PDA. Once I find out that once again another duct has reared it’s ugly head so to speak a number of thoughts run through my head. Should I treat it? With what? For how long? What if the first treatment doesn’t work? Should I have given prophylactic indomethacin? If I do that how any ELBWs will experience significant renal impairment or worse NEC based on that decision? Then we move into a completely different territory that occurs after the duct has been unsuccessfully treated. To ligate or not to ligate? With so many questions and so many conflicting papers in the literature some of which say the ductus is associated but not causative for this or that outcome it is no wonder I am still largely in the dark as to what is truly the best approach.
What about prophylactic indomethacin?
With respect to the use of prophylactic indomethacin the TIPP study clearly showed that while units could reduce the incidence of PDA and with in severe intraventricular hemorrhage the impact on neurodevelopment was unchanged. This was definitely unfortunate news as the trade off then to exposing all of the infants < 1000g in a unit to an increased risk of renal impairment and NEC would not be seemingly worth it. As PDAs are found more commonly in those ELBWs who are not exposed to antenatal steroids, a 2011 paper questioned whether provision of indomethacin prophylaxis only to those babies without steroids was published. Unfortunately the results were not as hoped as no benefit to this subgroup was noted.
Ibuprofen has been associated with less renal impairment and lower risk of NEC but unfortunately we do not have any long term outcome results from ELBWs treated with such therapy. It is promising though that the Cochrane review on the subject found a number of positive short term outcomes from the use of such treatment. In 7 studies included the rates of development of a PDA, repeat courses of NSAIDs and surgical ligations were all reduced with this therapy.
More recently several papers studying paracetamol (tylenol) as a medicine to promote ductal closure have been published but results have been mixed and the lack of large RCTs make it difficult to advocate for it’s regular use instead of ibuprofen or indomethacin. A cochrane review comparing oral ibuprofen to oral paracetamol has been published in 2015 and does show based on the two studies included that the drugs are likely equally efficacious in closing a ductus with an added benefit of paracetamol being less oxygen usage and hyperbilirubinemia compared to ibuprofen. Recent data in mice however linking autism to fetal exposure to paracetamol has necessitated longer term outcome data before this treatment can be recommended instead of the current ibuprofen or indomethacin.
What about the option of benign neglect?
Another option exists however which is to manage any symptoms resulting from the PDA and allow it to close on it’s own. This was the subject of a recent paper published in Archives of Diseases and Childhood Fetal and Neonatal Ed by Rolland et al. The authors of this study describe their experience retrospectively during a time in which there was intentional avoidance of treatment of any kind including ligation for the ductus. What this allows for is a comprehensive assessment of the natural history of the ductus in their cohort of 103 infants between 24-27 weeks gestational age.
Although the study began with 103 infants there were 12 infants (12% of the cohort) that died prior to 72 hours which was the time when the identification of the PDA would have been done. We do not know if these infants died from the PDA or not but it is fair to agree with the authors that unless prophylactic indomethacin was being used this outcome would not have been avoidable. Looking at the remainder of the group, 8 were found to have no PDA at 72 hours while an additional 13 had either no ECHO (10) or died (3) so were not followed. In the ten cases that did not have an ECHO the reason was the lack of respiratory support so presumably the ECHO result would have been irrrelevant to care. The remaining 70 are described in the following table where HNSPDA is a hemodynamically non significant PDA, HSPDA refers to a significant PDA and IDHS means insufficient data on the hemodynamic status although the PDA is still there.
Death before discharge
Survival at discharge with a PDA
Ligation of PDA
The paper is intriguing for a number of reasons. The first is that by an average age of two months 73% of the PDAs closed from the 70 patients that had documented persistence after 72 hours. We know that from the group of 91, 8 had closure at 72 hours which leaves 83 with a PDA. An additional 10 were not studied as mentioned above as they had no symptoms so we can assume they did not have a HSPDA. Of the three that died however we do not know if the PDA contributed. Looking at the 70 patients left 11 more patients died and 7 were discharged with a PDA. The authors do not disclose the fate of those additional 7. Did they have a ligation after discharge or not and by what method? If they were ligated this is still a positive outcome inn my my mind as the larger infant at that point would likely tolerate a surgical or catheter based closure much better with less morbidity.
It can also not be ignored that in this study the incidence of pulmonary hemorrhage was high at 25% and severe IVH in 21%. Both of these outcomes may be affected by the presence of a PDA so one important question raised here is an ethical one. Clearly many of the children studied who were not treated avoided complications related to treatment which is a good thing. The concern however is that by not treating there may have been excessive morbidity in those who developed the above complications and lacking from the study is follow-up of the survivors to see if their outcome. We also clearly don’t know what the PDA may have contributed to death in this study which is also clearly an important outcome to consider.
I wish I could give you the answer of what to do with these kids. Watch and wait or treat? I suspect in the end we will likely settle on a hybrid approach guided by information gleaned from Targeted Neonatal Echocardiography as was discussed in a post on the topic which can be found here. I think the future state will likely see us using a strategy of selecting some infants by risk categorization to receive prophylactic indomethacin, some to have TNE done between 48 – 72 hours with or without the use of biomarkers to identify those who are likely to get a HSPDA and then treat those and then a final group that we may watch.
What the above study adds to the literature though is that in this final category who we may watch and wait there is about a 75% chance that they will close on their own. If we can pick out the ones that are not HSPDA I suspect the spontaneous closure rate would be even higher. While I am grateful for the publication of this article for now I will continue to pick and choose as best I can which ducts we need to deal with and those we don’t. Hopefully with time and more knowledge my body sighs will be replaced by a look of confidence as I explain to families what is needed for their child.