EBNEO Commentary: Precision management of the patent ductus arteriosus in micropreemies

Management of the PDA in preterm infants remains a contentious topic despite randomised controlled trial (RCT) evidence to date failing to demonstrate any clinically meaningful benefit with early pharmacotherapy.1, 2 Controversy exists on whether existing RCT evidence on PDA pharmacotherapy can be applied to micropreemies born at the limits of viability (22–24 weeks gestation) given the lack of representation of this population in contemporary RCTs. Giesinger et al, in their single-centre cohort study make a strong case for a more nuanced approach to hemodynamic management of these vulnerable preterm infants. Most existing RCTs of PDA therapy have defined a symptomatic PDA based on characteristic clinical signs, along with echocardiographic evidence of increased PDA shunt volume.2 Unfortunately, the most used echocardiographic criteria, the PDA size and the left atrium to aortic root ratio have poor inter-rater reliability.3, 4 In addition, existing trials have not attempted to differentiate between PDAs with moderate versus high shunt volume, based on any clinical or echocardiographic criteria. Post hoc analyses of recent RCTs have suggested that infants exposed to a moderate-large shunt beyond the first week are at higher risk of adverse clinical outcomes such as death or BPD.5-7 The quaternary NICU at the University of Iowa have addressed majority of the above-mentioned issues through an early targeted hemodynamic management approach with due emphasis on the dynamic nature of PDA shunt physiology in the first few days resulting in more targeted use of not only PDA pharmacotherapy but also pulmonary vasodilators and vasopressors, especially in the first week, that possibly translated to a large reduction in death/severe BPD, severe IVH and a substantial improvement in survival free of severe morbidity. Though there is sufficient biological plausibility to explain such findings, causality should be inferred with caution. First, despite attempts to control for natural improvement over time and other potential confounders, there exists a risk for unaccounted confounding inherent to cohort studies with historical controls, unless a cross-over study is conducted with re-introduction of hemodynamic management practices of the historical cohort for a period of time.8 Second, it is important to note that in the cohort of 22–24-week GA infants, primary acetaminophen therapy was effective in only 50% infants, and 53% of infants had a persistent hsPDA at 7 days. Their data aligns with recent trials demonstrating suboptimal PDA closure efficacy of intravenous acetaminophen in very preterm infants9; thereby lending credence to the suspicion that reduction in shunt exposure was unlikely to have solely contributed to a 23% absolute reduction in death/severe BPD. In conclusion, results of Giesinger study calls for a closer examination of the PDA physiology in this population of micropreemies with vastly different physiology compared with the ones mostly enrolled in RCTs; and despite growing calls for abandoning further clinical trials on PDA management, the current evidence underscores the need to clearly establish which PDA shunts, if any, are truly pathological and pursue further clinical trials that include micropreemies at the highest risk of PDA-attributable morbidities and explore highly effective and safe shunt elimination strategies. URL LINK: https://ebneo.org/ebneo-commentary-precision-management-of-the-patent-ductus-arteriosus-in-micropreemies/. This commentary is a tribute to the late Dr Regan Giesinger's unwavering devotion towards improving the outcomes of the smallest and sickest babies. In her relatively short career, she had advanced the field of neonatal hemodynamics in a manner that has not only touched the lives of hundreds of babies but has also opened several avenues for future hemodynamic research. She will be dearly missed by the neonatal community. None. The author has no conflicts of interest to disclose.

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