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.

Keywords: bronchopulmonary dysplasia; necrotizing enterocolitis; newborn; premature birth; retinopathy of prematurity.

Figure 1.

Drug protocols used to treat PDA.

Figure 2.

Flow diagram of patient entry into the study. *Percentage of eligible infants who were excluded owing to previous NEC/intestinal perforation or to dopamine-dependent hypotension, hydrocortisone-dependent hypotension, active pulmonary hemorrhage, abnormal renal function, or profound thrombocytopenia/coagulopathy at the time of enrollment. Some infants had more than 1 exclusion criterion.

Figure 3.

Weekly incidence of intubation and mechanical ventilation among in the CT and ERT groups after randomization.

Figure 4.

Weekly respiratory severity scores in the CT and ERT groups after randomization. The box-and-whisker diagram displays minimum, first quartile, median, third quartile, and maximum values. Respiratory Severity Score: mean airway pressure × FiO₂.

Figure 5.

Weekly incidence of moderate-to-large PDA shunts in the CT and ERT groups after randomization. Infants were delivered between 23^0/7 and 25^6/7 weeks (ie, <26 weeks) and between 26^0/7 and 27^6/7 weeks (ie, ≥26 weeks) gestation.