PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age

Abstract

Objective To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given. Study design A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial. Results At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%). Conclusions In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation. Trial registration ClinicalTrials.gov: NCT01958320.

PDA Closure in ELBW Infants: If, When, and How to Do It

“…Persistent PDA in ELBW infants with respiratory distress syndrome (RDS) has been linked to numerous pulmonary complications, including increased flow and pressure to the pulmonary vascular bed, increased lung water, decreased lung compliance [13,14], prolonged ventilation [15], worsening pulmonary disease [16], pulmonary hemorrhage [13][14][15][16], severe bronchopulmonary dysplasia (BPD) [17], and death [17].…”

“…While numerous sequelae have been associated with the presence of a moderateto-large PDA in ELBW infants, it remains unclear whether these are the result of having a PDA or are the natural consequences of prematurity. Previous randomized control trials (RCT) suggest that long-term morbidities are not affected by shortterm exposure to a PDA (3-4 days) [13,23], however these conclusions are confounded by early spontaneous closure of the PDA, failure to account for differing shunt sizes, and the early use of rescue treatments, or a lack of equipoise, on behalf of the physicians [13]. There is no consensus on the exact consequences of a PDA in the premature infant, but most agree that persistent and significant left-to-right shunting of blood in the ELBW infant is not helpful [24].…”

“…In 2018, Ronald Clyman designed the PDA Tolerate Trial [13] to further examine early routine therapy versus conservative management by controlling for variables that had confounded many of the previous RCTs. Inclusion criteria was limited to infants with a moderate-to-large PDA that did not close spontaneously within the first week.…”

“…With evidence mounting against the use of COX inhibitors and surgical ligation, the trend towards permissive conservative observation of this lesion has developed, reserving surgery for only the most severe cases [13][14][15][16][17]32]. Unfortunately, recent data suggests that this approach is associated with an increased risk for the development of chronic lung disease and death, especially in infants born ≤26 weeks' gestation [8][9][10][11][12][13][14][15][16][17]. More recently in the United States, survival of infants born as early as 22 weeks' gestation is now possible [33], making the need for effective PDA therapy in this high risk, ELBW population more important than ever.…”

Persistierender Ductus arteriosus des Frühgeborenen – Therapiestrategien

“…B. keine Outcome-Verbesserung durch pharmakologische Behandlung bei moderatem bis großem PDA im Vergleich zu einer konservativen Therapie. Die pharmakologische Therapie war sogar mit einem verzögerten Nahrungsaufbau und einer höheren Mortalität assoziiert [5].…”