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BACKGROUND: Several small randomized controlled trials (RCTs) and observational studies have compared high (15-20/7.5-10/7.5-10 mg/kg/dose) versus standard dose (10/5/5 mg/kg/dose) ibuprofen for patent ductus arteriosus (PDA) closure, with limited evidence on efficacy and safety. OBJECTIVE: To systematically review and meta-analyze studies of high versus standard dose ibuprofen for the closure of PDA in preterm infants. METHODS: Databases were searched for RCTs and observational studies assessing high compared to standard dose of ibuprofen for PDA closure for preterm infants until August 2021. The primary outcome was failure of PDA closure after the first course of ibuprofen. The secondary outcomes were the failure of PDA closure after a second course of ibuprofen, rates of PDA ligation, all-cause mortality prior to hospital discharge, bronchopulmonary dysplasia, necrotizing enterocolitis, bleeding disorders, oliguria, and serum creatinine after treatment. RESULTS: There were 6 studies with 369 patients (3 RCT, N = 190; 3 observational studies, N = 179). Compared to standard dose, high dose ibuprofen did not significantly decrease the failure rate of PDA closure in preterm infants after the first course (Relative risk (RR) 0.74, 95% confidence interval (CI) 0.53 –1.03, 6 studies, N = 369). High dose ibuprofen significantly decreased the rates of PDA ligation compared to standard dose (RR 0.33, 95% CI 0.16 –0.70, 5 studies, N = 309). INTERPRETATION: Based on low-grade evidence, high dose ibuprofen may more effectively reduce rates of PDA ligation compared to standard dose with no increase in adverse effects, neonatal morbidities and mortality. [ABSTRACT FROM AUTHOR]

Complications of preterm birth are the main cause of death in children before the age of 5 years. Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows ventilator and O2 therapy for acute respiratory failure, is the most common complication of extreme prematurity. BPD accounts for life-long morbidity and lacks effective treatment. Preclinical data suggesting lung protective effects of human umbilical cord (UC)-derived mesenchymal stromal cell (MSC) form the rationale for the clinical translation of UC-MSCs for BPD. Helping Underdeveloped Lungs with Cells (HULC) was a Phase I, open-label, multicentre, dose-escalation trial to assess the safety and feasibility of a single, intravenous (i.v.) injection of allogeneic human UC-MSCs in preterm infants at high risk of developing BPD. Patients were included if they were born <28 weeks gestation, still intubated and on mechanical ventilation with FiO2 30% or higher between postnatal day 7-28. The first three patients received low dose 1.0 × 106 UC-MSC/kg, the next three patients received intermediate dose (3.0 × 106 UC-MSCs/kg), and the final three patients received high dose (10 × 106 UC-MSCs/kg). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT04255147. Nine preterm infants were enrolled between Oct 13, 2022 and Nov 6, 2023 at a mean gestational age of 24.5±1.3 weeks and a mean birth weight of 647±131g. UC-MSC were given at a mean of 19.3±6.1 days after birth. No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. There were no deaths. All patients had BPD. In the low dose group, all 3 patients had severe BPD (FiO2>30% or positive pressure at 36 weeks corrected). In the highest dosing group, no patient had severe BPD. Complications usually associated with prematurity included patent ductus arteriosus (n=3), necrotizing enterocolitis (n=1), severe retinopathy of prematurity (stage 3 or higher, n=2), intraventricular hemorrhage grade 1-2 (n=3), late-onset sepsis (n=5). None of these were MSC-related. In conclusion, a single i.v. infusion of allogeneic UC-MSCs was well tolerated in nine extreme preterm infants at high risk of developing BPD. A phase 2 trial is warranted to test the efficacy and safety of 10 × 106 UC-MSC/kg in a larger patient population. [ABSTRACT FROM AUTHOR]