Thoughts on NSAIDs for PDA
The patent ductus arteriosus in prematurity - Is it unethical to administer NSAIDs?
Disclaimer – this is only my own opinion, and I truly believe that we are all scientists that try to do the best appraisal of the evidence in order to provide the most optimal care to our vulnerable patient populations.
After carefully reviewing the literature (some references below - 1 to 7, but there are 100s), I believe there are numerous publications outlining that 1000s of premature infants in randomized control trials have failed to show any benefits from exposing these newborns to prophylactic, early or targeted medications to attempt acceleration of ductal closure. Actually, the preliminary results of the Beneductus trial in Europe (presented at the Pediatric Academic Societies 2021 in Denver by Pr Willem de Boode), has demonstrated that there may even be an increase in harm when exposing extreme premature infants to early ibuprofen (even with a targeted approach). The study was very well done, and there was almost no open-label treatment.
Could these medications be toxic, and not even provide any sort of benefit to these vulnerable infants? Possibly... And likely according to what I am getting from these studies. Is there a subgroup (very limited number of infants) that may benefit from accelerated closure by other means? Some of the studies looking at catheter-based approaches or paracetamol/acetaminophen are ongoing (but will unlikely show any benefits in my biased opinion).
For all these reasons, I strongly believe that NSAIDs, are not the way to go. Our local practice has been to abandon the use of these toxic medications. They are known to cause systemic vasoconstriction (undifferentiated, reference 8-9, but there are so many articles on this). They are associated with increased spontaneous intestinal perforation, end-organ ischemia and renal dysfunction ( in part due to the renal hypoxic vasoconstriction that is sustained).
Of course, any care bundles have to be taken into context. We do not just “ignore” the ductus, we have implemented successfully multiple care guidelines for our preterm newborns. We have an extensive golden hour protocol. We have trained all our health care professionals to be expert at the most extreme premature newborns (nurses, nurse practitioners, nutritionists, respiratory therapists, medical trainees, etc.). We have guidelines standardizing the care of our extreme premature population for the first week of life and beyond. We have clinical pathways standardizing ventilation, investigations, caffeine use, nutrition (with a rapid exposure to breastmilk and aiming to get to full feed in the first 7 days), etc. We are aggressive at obtaining breast-milk and promoting early and prolonged skin-to-skin care. Our rate of intubation in the delivery room (DR) is very low, and most of our newborns <29 weeks are brought to the NICU (including those <26 weeks) on bubble CPAP. With bCPAP, it is quite easy to install the cPAP in the delivery room and transport the baby to the unit. It is also a reliable way to sustain adequate peep, avoiding multiple disconnections and loss of FRC. (There is also some data that the frequency of oscillation, which changes with underlying pulmonary compliance, provides some benefits to the infant and more articles showcasing its benefits in the premature population). I have seen a dramatic drop in the need to intubate these infants (especially those born at 26 weeks and more). We even have newborns 23 weeks arriving to the NICU on bCPAP! These infants seem to have a much smoother transition (than what I was used to in my previous practice), as well as optimal recruitment and oxygenation. The drop of PVR occurs possibly more smoothly, allowing for less torrential left to right shunt via the ductus that eventually spontaneously constricts to various degree (until it finally closes at various ages, but often before 36 weeks). I scan almost all the <29 weeks infants in the unit at 10 days and 36 weeks, and it is extremely rare that the ductus is still patent.
We only provide intubation and surfactant in those infants with the most severe respiratory distress syndrome (our protocol has been published, references 10-11). As such, with FiO2 above 50% consistently (or other signs of significant respiratory distress or apneas), these infants get intubated and get surfactant. With a more selected population of infants exposed to surfactant, there is less acute drop in the pulmonary vascular resistance, which makes our rate of pulmonary hemorrhage low (6%) in our extreme premature population (same rate in the <26 weeks newborns). These events of pulmonary hemorrhage often occurs in infants that are outborn, and rarely yield to catastrophic decompensation since they are often these babies that remain intubated and found to have traces of blood upon suction. We do not restrict the total fluid intake (aiming 150-160 mL/kg/day total) and we aim for good nutrition for adequate growth and caloric intake. Patient gets ventilated in volume-guarantee when mechanically-ventilated and extubation occurs after the 72 hours window (in the <27 weeks newborns), once they do get intubated (we are often more rapid at extubating those 27-28 weeks infants, but they so rarely do get intubated in the first place to be honest). Extubation is deemed ready on a pulmonary perspective if FiO2 is <35%, mean airway pressure <10 and drive is present (that is not a set practice guideline). Infants that remain dependent on mechanical ventilation will receive low dose dexamethasone at >14 days (median 21 days of initiation) to get off mechanical ventilation.
Initially, I was quite skeptical about the absence of medical attempt to close the ductus. It my hemodynamics mind, it did not make sense. I compared the rates of death or BPD of my unit to the ones of another unit and found that there may have been an increase of this rate after the adoption of the policy compared to the status quo in another unit. The other unit, though, had excessively higher rate of death or BPD all throughout the 2 periods (so very hard to increase when your baseline is already 80-90% death or BPD!). The rates of those infants exposed to a no NSAIDs policy, was still dramatically low in terms of death or BPD. Also, the unit adopting the conservative policy, had seen a dramatic increase in the admission of outborn infants 23-24 weeks in the 2015, 2016, 2017 period (following the move to a much bigger single-bed unit, fusing 2 previous units). As we all know, these infants are at the highest risk for death or BPD. The previous EPOCH using NSAIDs had very low numbers of infants born at 23 weeks (most of them being inborn and selected because of their "good profile" to survive). We now care for infants <25 weeks, <600 grams at birth that are born with already very significant medical burden (severe maternal hypertensive or rheumatological conditions, extremes of obesity or diabetes, maternal oncological processes, maternal ECMO, extremely severe growth restriction, twins with TTTS, triplets, etc.). We are the only center in my province that can provide ICU care to the mother with all subspecialty (liver/renal/cardiac/oncology), as well as all array of medical/surgical care to these infants. As such, we do attract some of the most complex cases. Also, as you all know, the association between prematurity-related averse outcomes is logarithmically associated with the degree of immaturity... so I did remain with a doubt in this relative increase in the outcome of death or BPD in the EPOCH 2...
As such, humble to dig more into the question, I recently published the updated follow-up data of our approach (adding the numbers of 2018 and 2019) since we moved to this new unit (single room). Our BPD rates kept on declining and they were actually were very good despite the high admission rate of infants 23-24 weeks that was maintained through the years. We had a 32% death or BPD in those <29 weeks… Further, we only had 7% of infants <26 weeks that had Grade 3 BPD as per the new NICHD classification! Looking at national rates, we have one of the lowest rate of mortality in this high risk population (despite those factors that I have exposed earlier regarding the complexity of the population we care for). These are amongst the best reported outcomes of this particularly vulnerable population in Canada. Our NEC rates are also consistently very low in this population as per our annual report. Our IVH rates are within national average (disclaimer: many of the <26 weeks outborn infants in our catchment area are re-routed to our centre, and as such, close to 20% of the <26 weeks admitted are outborns). The majority (>90%) of these infants underwent spontaneous closure. Since 2015, we have had only 1 premature infant (born <29 weeks) requiring a tracheostomy (and we have admitted since that time: 400 babies <29 weeks, out of which there are 40 infants <24 weeks, 50 at 24 weeks, and 60 born at 25 weeks). Further, we recently reported on our population with pulmonary hypertension, and compared to previous reports, our mortality rate within this subgroup was extremely low. There were only 24 infants with >2/3 systemic pulmonary pressure estimates at the 36 weeks echocardiography (out of a source sample of 387 infants, 8%). Reported literature quotes that mortality can be up to 25% in this subgroup, while only 3 infants did not survive among these 24...
For some reason, the PDA debate is very emotional for many. My physiological mind tells me that the left to right shunt through the ductus is probably not great for these infants with such vulnerable status in the post-natal setting. However, the attempt at accelerating its closure (with invasive methods, or with potentially toxic medications) does not confer an advantage and seem to be at their detriment. I am now quite confident about the approach of not using NSAIDS in this population. With all the studies out there, it is time to accept the null hypothesis and stop loosing so much resources, time, energy, money on studying yet-again NSAIDS that have been shown in countless well designed randomized studies to not benefit these babies! No matter how much we would like these medications to benefit them. At this point, one may argue that it is unethical to expose a patient to such medication. It is also not a judicious use of scarce research resources to try to enrol infants in yet another study that was already done, to replicate negative results (or worst, increase harm)
Regarding cath-closure, I am worried that we will be intervening on very small infants that are transitioning, potentially exposing them to interventional complications for no benefits. I hope to be wrong... I have seen some infants post-embolization of the occluder (not good)... I have also seen some premature infants loosing a limb due to vascular injury when attempting ductal closure at early age. I have heard some centres with mortality and low output from valvular injury, atrial rupture and sustained arrhythmia...
Sankar MN, Bhombal S, Benitz WE. PDA: To treat or not to treat. Congenit Heart Dis. 2019 Jan;14(1):46-51. doi: 10.1111/chd.12708. PMID: 30811796.
Benitz WE. Hey, Doctor, Leave the PDA Alone. Pediatrics. 2017 Aug;140(2):e20170566. doi: 10.1542/peds.2017-0566. Epub 2017 Jul 12. PMID: 28701391.
Sankar MN, Benitz WE. Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment? J Perinatol. 2020 Dec;40(12):1863-1870. doi: 10.1038/s41372-020-00848-z. Epub 2020 Oct 6. PMID: 33024260.
Benitz WE, Bhombal S. The use of non-steroidal anti-inflammatory drugs for patent ductus arteriosus closure in preterm infants. Semin Fetal Neonatal Med. 2017 Oct;22(5):302-307. doi: 10.1016/j.siny.2017.07.004. Epub 2017 Jul 17. PMID: 28724506.
Chock VY, Goel VV, Palma JP, Luh TM, Wang NA, Gaskari S, Punn R, Silverman NH, Benitz WE. Changing Management of the Patent Ductus Arteriosus: Effect on Neonatal Outcomes and Resource Utilization. Am J Perinatol. 2017 Aug;34(10):990-995. doi: 10.1055/s-0037-1601442. Epub 2017 Apr 4. PMID: 28376547.
Mitra S, Scrivens A, von Kursell AM, Disher T. Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants. Cochrane Database Syst Rev. 2020 Dec 10;12(12):CD013278. doi: 10.1002/14651858.CD013278.pub2. PMID: 33301630; PMCID: PMC8812277.
Evans P, O'Reilly D, Flyer JN, Soll R, Mitra S. Indomethacin for symptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev. 2021 Jan 15;1(1):CD013133. doi: 10.1002/14651858.CD013133.pub2. PMID: 33448032; PMCID: PMC8095061.
Nilsson F, Björkman S, Rosén I, Messeter K, Nordström CH. Cerebral vasoconstriction by indomethacin in intracranial hypertension. An experimental investigation in pigs. Anesthesiology. 1995 Dec;83(6):1283-92. doi: 10.1097/00000542-199512000-00019. PMID: 8533921.
Kraaier V, Van Huffelen AC, Wieneke GH, Van der Worp HB, Bär PR. Quantitative EEG changes due to cerebral vasoconstriction. Indomethacin versus hyperventilation-induced reduction in cerebral blood flow in normal subjects. Electroencephalogr Clin Neurophysiol. 1992 Mar;82(3):208-12. doi: 10.1016/0013-4694(92)90169-i. PMID: 1371441.
Nouraeyan N, Lambrinakos-Raymond A, Leone M, Sant'Anna G. Surfactant administration in neonates: A review of delivery methods. Can J Respir Ther. 2014 Fall;50(3):91-5. PMID: 26078618; PMCID: PMC4456838.
Germain A, Nouraeyan N, Claveau M, Leone M, Sant'Anna G. "Optimal surfactant delivery protocol using the bovine lipid extract surfactant: a quality improvement study". J Perinatol. 2021 Jan;41(1):17-23. doi: 10.1038/s41372-020-00846-1. Epub 2020 Oct 3. PMID: 33011749; PMCID: PMC7532933.