Early closure mechanisms of the ductus arteriosus in immature infants

Abstract

Aim According to experimental studies, cardiopulmonary distress decreases after closure of patent ductus arteriosus. However, early closure of the ductus using ibuprofen or indomethacin has failed to increase survival without serious morbidity. We review relevant data aiming to define optimal early management strategies that promote early closure of ductus arteriosus without serious adverse effects. Methods Literature in English was searched selectively focusing on the potential of using acetaminophen for early closure of the ductus. Results Prophylactic ibuprofen or indomethacin intended to close the ductus, predisposes infants to ischaemia, bleeding and immune dysfunction. Acetaminophen appears to have a similar efficacy as indomethacin or ibuprofen, and all three dose‐dependently constrict the ductus. Ibuprofen and indomethacin cause non‐specific inhibition of prostaglandin synthesis, while acetaminophen predominantly inhibits prostaglandin E synthesis. Owing to low CYP450 activity in infancy, acetaminophen toxicity has been rarely evident. However, increasing the dosage increases the oxidative stress. We review prophylactic treatments that may increase the safety and efficacy of acetaminophen. These include vitamin A, cysteine and glutamine, and low‐dose corticosteroid supplementation. Conclusion The current challenge is to define a safe perinatal management practice that promotes cardiorespiratory adaptation in immature infants, particularly the seamless closure of the ductus before significant cardiopulmonary distress develops.

Management Practices During Perinatal Respiratory Transition of Very Premature Infants

“…Bowel perforations have been particularly associated with ibuprofen. NSAIDs also potentially complicate the PDA closure, as they prevent adherence-promoting thrombosis within the intima of the constricted PDA ( 100 ).…”

Management of patent ductus arteriosus in very premature infants: An ongoing conundrum

“…In foetal rodents and rabbits, Heymann and Rudolph was demonstrated that prostaglandin synthesis inhibition resulted in PDA constriction 4 . As and performed observational studies using indomethacin and aspirin on human preterm infant manifesting clinical signs of a PDA 5 . However, pharmacologic closure of the PDA using indomethacin was fraught by adverse renal toxicity and lack of an intravenous preparation initially limited its use.…”

“…Hallman et al reviewed the evolution of pharmacologic closure of the PDA with indomethacin, various formulations of Ibuprofen and more recently Paracetamol (acetaminophen) 5 that was initially described by Hammerman and coworkers 6 . Differences in preparations, route of dosing frequency and timing of administration after recognition of a haemodynamically significant PDA in very premature infants using various study designs were inconsistent in finding beneficial effects when meta‐analyses of combined studies were reported 7,8 .…”

“…Differences in preparations, route of dosing frequency and timing of administration after recognition of a haemodynamically significant PDA in very premature infants using various study designs were inconsistent in finding beneficial effects when meta‐analyses of combined studies were reported 7,8 . However, several single‐centre trials did document improvements in reducing pulmonary haemorrhage, severe intraventricular haemorrhage and chronic lung disease in treated infants versus those receiving placebo as reported 5 . In a multicenter exploratory, randomised controlled trial of various pharmacologic agents used for PDA closure versus placebo in 202 very preterm infants (<28 weeks' gestation) of whom 49% were intubated on IMV and 48% required nasal ventilation of CPAP, treated at 6–14 days after birth, no differences in rates of ligation, the presence of PDA at hospital discharge, nor any differences in NEC, BPD, BPD and/or death, or death were found among those receiving pharmacologic closure versus placebo‐treated infants, while the rate of late‐onset neonatal sepsis was increased among treated infants 9 .…”