The Effect on Extubation of Early vs. Late Definitive Closure of the Patent Ductus Arteriosus in Premature Infants: A Target Trial Emu-lation Using Electronic Health Records and A Target Trial Emulation Comparing High-frequency Jet Ventilation Management Strategies for Respiratory Acidosis among Neonates with Respiratory Failure

Abstract

It’s well established that the key advantages of a randomized trial include: marginal exchangeability between groups, clear specification of time zero, and synchronization of eligibility check and treatment assignment with time zero. These features become even more apparent when considering the challenges of drawing causal conclusions from observational data. A reliable approach to maintaining the key attributes of randomized trials in observational analyses is to design them in a way that explicitly emulate a hypothetical randomized trial aimed at answering the causal research question — the target trial. Premature infants are often referred for the definitive procedural closure of the patent ductus arteriosus (PDA) with the failure of, or contraindication to, pharmacotherapy and the inability to wean respiratory support. However, once this need is identified, the importance of expedited closure is unclear. We first specified a hypothetical randomized trial (the “target trial”) that would estimate the effect on extubation of early (0–4 days from referral) vs. late (5–14 days from referral) definitive PDA closure. We then emulated this target trial via inverse probability (IP) weighting, using a single-institution registry of premature infants (born weeks or with a birth weight 1500 g) who underwent the definitive closure of PDA between January 2014 and October 2023. The objective of this study was to compare the effect of the timing of definitive closure (i.e., surgical ligation or de-vice occlusion) on early respiratory outcomes in premature infants without complex congenital cardiac disease. High-frequency jet ventilation (HFJV) is often used in neonatal intensive care units (NICUs) to treat respiratory failure. In neonates initiating HFJV for hypercarbic respiratory failure, clinicians aim to adjust ventilator settings to achieve a gradual reduction in pCO₂. Rapid correction with a large shift in pCO₂ may lead to cerebrovascular spasm and increase the risk of neurovascular injury. However, specific management of HFJV peak inspiratory pressure (PIP) varies across institutions. Here, we use EHR data and aim to compare two dynamic PIP management strategies by emulating a progmatic target trial. We illustrate the use of inverse probability (IP) weighting to adjust for time-varying confounding.