Precision management of the patent ductus arteriosus in micropreemies
Giesinger RE, Hobson AA, Bischoff AR, Klein JM, McNamara PJ. Impact of early screening echocardiography and targeted PDA treatment on neonatal outcomes in “22-23” week and “24-26” infants. Semin Perinatol. 2023;47(2):151721. PMID 36882362
Souvik Mitra MD, MSc, PhD, FRCPC
Department of Pediatrics, Department of Community Health & Epidemiology
Dalhousie University & IWK Health, Halifax, Canada
E-mail: firstname.lastname@example.org ; email@example.com
TYPE OF INVESTIGATION
In (P) preterm infants born between 22+0 – 23+6 weeks of gestation, does management of a hemodynamically significant patent ductus arteriosus (hsPDA) based on (I) early hemodynamic screening (HS) using targeted neonatal echocardiography (TnECHO) versus (C) echocardiographic screening when clinically symptomatic, improve (O) the primary composite outcome of death before 36 weeks or severe bronchopulmonary dysplasia (BPD)?
• Design: Retrospective cohort study
• Allocation: Cohort of patients meeting inclusion criteria (see below) between October 2018 and April 2022 compared to a historical control (HC) group (between January 2010 to December 2017)
• Blinding: None
• Follow-up period: 36 weeks postmenstrual age
• Setting: Single quaternary Neonatal Intensive Care Unit (University of Iowa)
• Patients: Preterm infants born between 22+0 – 23+6 weeks of gestation were eligible unless major anomalies or congenital heart disease were present, or resuscitation was either incomplete or not provided. Of note, the study also analyzed the outcomes of infants born between 24+0 – 26+6 weeks of gestation as an exploratory comparative subgroup.
• Intervention: Early hemodynamic screening (HS) using targeted neonatal echocardiography (TnECHO)
• Primary outcome: Composite of death before 36 weeks or severe bronchopulmonary dysplasia (BPD) (defined using the Jensen criteria as grade 3)
• Secondary outcomes: Death; severe BPD; survival free of morbidity (severe IVH using Papile’s criteria as grade 3 or 4; any necrotizing enterocolitis, grade 3 BPD using the Jensen criteria), pulmonary hemorrhage, pneumothorax, PDA therapy (medical and interventional), intestinal complications and retinopathy of prematurity requiring treatment
• Analysis and sample size: Univariate analysis was conducted for baseline characteristics, concomitant neonatal interventions and clinical outcomes. In addition, for the primary outcome, an interrupted time series analysis was conducted to account for natural improvement over time due to known and unknown factors. No sample size calculation was provided.
• 189 infants were included in the 22+0-23+6 (n=73 HS, n=116 HC) cohort. Infants in the HC cohort had lower birth weight (p=0.036), while in the HS cohort there was increased use of maternal magnesium sulfate (p=0.002) and delayed cord clamping (p=0.005).
• All patients in the HS epoch were evaluated using TnECHO between 12-18h postnatal age and managed according to a physiology-based algorithm that included an echocardiography-based scoring system to assess degree of PDA shunt volume. The HC infants were assessed by echocardiography at the discretion of the clinical team.
• There was 23% absolute reduction in the primary outcome of death or severe BPD (HS 23% vs HC 46%; p=0.002) in the 22+0-23+6 cohort.
• With regards to secondary outcomes, there was 23% absolute increase in survival without severe morbidity (HS 73% vs HC 50%; p=0.002), 20% absolute reduction in severe IVH (HS 7% vs HC 27%; p<0.001), 26% absolute reduction in severe BPD (HS 61% vs HC 87%; p=0.001), 10% absolute reduction in NEC (HS 1% vs HC 11%; p=0.01); 24% absolute increase in PDA pharmacotherapy (HS 88% vs HC 64%; p<0.001), but a 14% absolute reduction in interventional PDA closure (HS 33% vs HC 47%; p<0.001) in the 22+0-23+6 cohort.
• After adjustment of potential confounders and year of birth, use of early hemodynamic screening predicted a higher likelihood of survival free from severe BPD (Odds ratio 5.1 [95% CI, 1.3 to 20.4]; p=0.023)
The authors conclude that early hsPDA diagnosis and physiology-targeted treatment using an early hemodynamic screening approach in micropreemies born between 22+0 – 23+6 weeks of gestation may improve clinically meaningful outcomes, and consequently, highlight the need for further examination of early echocardiography directed therapy of hsPDA in this population.
Management of the PDA in preterm infants remains a contentious topic despite randomized 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-center 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 infants(9); 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 to 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.
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.
1. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol. 2010 Apr;30(4):241–52.
2. Mitra S, de Boode WP, Weisz DE, Shah PS. Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews. Cochrane Database Syst Rev. 2023 Apr 11;4(4):CD013588.
3. de Freitas Martins F, Ibarra Rios D, F Resende MH, Javed H, Weisz D, Jain A, et al. Relationship of Patent Ductus Arteriosus Size to Echocardiographic Markers of Shunt Volume. J Pediatr. 2018;202:50-55.e3.
4. Zonnenberg I, de Waal K. The definition of a haemodynamic significant duct in randomized controlled trials: a systematic literature review. Acta Paediatr. 2012 Mar;101(3):247–51.
5. Liebowitz M, Katheria A, Sauberan J, Singh J, Nelson K, Hassinger DC, et al. Lack of Equipoise in the PDA-TOLERATE Trial: A Comparison of Eligible Infants Enrolled in the Trial and Those Treated Outside the Trial. J Pediatr. 2019;213:222-226.e2.
6. Clyman RI, Kaempf J, Liebowitz M, Erdeve O, Bulbul A, Håkansson S, et al. Prolonged Tracheal Intubation and the Association Between Patent Ductus Arteriosus and Bronchopulmonary Dysplasia: A Secondary Analysis of the PDA-TOLERATE trial. J Pediatr. 2020 Oct 27;
7. Clyman RI, Hills NK, Cambonie G, Debillon T, Ligi I, Gascoin G, et al. Patent ductus arteriosus, tracheal ventilation, and the risk of bronchopulmonary dysplasia. Pediatr Res. 2022 Feb;91(3):652–8.
8. Bernal JL, Cummins S, Gasparrini A. Interrupted time series regression for the evaluation of public health interventions: a tutorial. Int J Epidemiol. 2017 Feb;46(1):348–55.
9. Jasani B, Mitra S, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev. 2022 Dec 15;12:CD010061.
Conflict of interest statement
The author has no conflicts of interest to disclose