Continuous Infusion of Ibuprofen for Treatment of Patent Ductus Arteriosus in Very Low Birth Weight Infants

Abstract

Background: Ibuprofen (IBU) has proved as effective as indomethacin in the pharmacological closure of hemodynamically significant patent ductus arteriosus (HsPDA), with an efficacy inversely related to gestational age (57-89%). Objective: This study aimed to establish whether continuous infusions of IBU could be more effective in very low birth weight infants with no additional adverse effects and reduce the need for surgical ligation. Methods: A prospective, randomized, double-dummy study was conducted on 112 very low birth weight infants (mean gestational age 27.2 weeks, SD 2; birth weight 1,019 g, SD 330) with HsPDA, 56 of whom were given IBU in conventional 15-min intermittent boluses, while the other 56 were administered IBU as a 24-hour continuous infusion, both at standard doses (10/5/5 mg/kg). Extensive echocardiography was performed before and after treatment, and adverse effects were monitored. Results: Pharmacological PDA closure was achieved after 1 or 2 IBU courses in 36 of 56 infants (64.3%) after bolus administration and in 46 of 55 (83.6%) after continuous infusion (p = 0.020), and in 9 of 26 (34.6%) and 24 of 30 (80.0%), respectively, in the infants with a gestational age of 23-27 weeks (p = 0.006). Sustained pharmacological closure was observed in 38 of 56 infants (67.9%) after bolus IBU and in 47 of 55 (85.5%) after continuous infusion (p = 0.029). Surgical ligation was used less after continuous infusion than after bolus IBU (5.5 vs. 19.6%; p = 0.024). The continuous infusion group had fewer symptoms of necrotizing enterocolitis (NEC), especially in the more preterm infants, while other neonatal morbidity and mortality rates were similar. Conclusion: Continuous IBU infusion is more effective than standard boluses for sustained closure of HsPDA, with fewer NEC symptoms and less need for surgical ligation in very low birth weight infants.

Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm Neonates

“…Early use of ibuprofen vs its use when PDA became significant resulted in a reduction in oxygen use of 2 days in the first 28 days after birth. A further study 64 compared bolus with continuous infusion of ibuprofen and reported a higher rate of sustained closure after continuous infusion (68% vs 86%, P = .03). However, no other neonatal outcomes were affected in any of these studies.…”

Letting post-marketing bridge the evidence gap: the case of orphan drugs: Table 1

“…After the marketing authorisation, five small single centre trials, [19][20][21][22][23] two systematic reviews with meta-analyses, 24 25 and one observational study 26 were published. One of the trials found that continuous infusion of ibuprofen was more effective and just as safe as the bolus dose; in a second trial ibuprofen proved as effective as indomethacin, while in two trials paracetamol was as effective as ibuprofen but safer.…”

Simulation-based suggestions to improve ibuprofen dosing for patent ductus arteriosus in preterm newborns

“…Our proposed maintenance dosage of 4 mg kg −1 every 12 h, leads to comparable trough concentrations with 10 mg kg −1  day −1 every 24 h, but with 22% lower peak concentrations. Secondly, continuous ibuprofen administration has been shown to be more effective than intermittent by Lago et al [13] even without a loading dose, leading to 84 vs 64% PDA closure, respectively. The higher responsiveness following a more stable ibuprofen exposure is confirmed by the counterintuitive finding of higher closure rates following oral than intravenous administration, which is thought to be caused by the more graduate absorption following oral intake [36].…”