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

Abstract

As early as the 1960s, many neonatologists recognised the patent ductus arteriosus (PDA) as a complication of what later became designated as ‘respiratory distress syndrome’. It was not until more extensive use of intermittent mandatory ventilation (IMV) and continuous positive airway pressure (CPAP) that the concept of pulmonary overcirculation via the PDA complicated ventilatory management and emerged as a major complication in the fluid and nutritional management of the smallest preterm infants. The use of IMV and CPAP kept these very small preterm infants alive for a sufficient interval (usually 4– 7 days) allowing for a decrease in Fi02 and mean airway pressures before the adverse haemodynamic effects of the PDA on worsening cardiopulmonary function to be appreciated. Chest radiographs showed clearing of the ‘ground glass’ with a small heart, to one of an enlarging heart and pulmonary oedema owing to the lefttoright shunting across the PDA.1 Until the 1970s, it was assumed that the ductus arteriosus was a passively open channel during foetal life that constricted postnatally by undefined molecular mechanisms when the newborn infant experienced an abrupt rise in oxygen saturation after the first breaths after birth as documented in the newborn guinea pig by Kennedy and Clark.2 Studies by Heymann and Rudolph documented responsiveness of isolated PDA strips to oxygen and that this effect was not altered by acetylcholine or norepinephrine.3 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 metaanalyses of combined studies were reported.7,8 However, several singlecentre 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 placebotreated infants, while the rate of lateonset neonatal sepsis was increased among treated infants.9 Developmental followup of 288 infants <28 weeks at birth in a randomised trial of ibuprofen or placebo treatment for a large PDA was accessed at 24 months and while fewer infant in the treatment group had a lower incidence of PDA, less pulmonary haemorrhage, but there were no differences in the number of infants surviving without cerebral palsy.10 These findings were unexpected as brain volume among infants undergoing pharmacologic closure was preserved, while those in the control groups had reduced cerebellar volume, but no differences in the maturation of the posterior limb of the internal capsule attributed to longstanding suboptimal cerebral oxygenation due to a PDA.11 Hallman et al reviewed the current recommendations against prophylactic closure of the PDA shortly after birth. He cites Benitz12 who advocates for ‘letting nature take its course’ and let the ductus arteriosus close spontaneously and not to interfere. He notes that the PDA spontaneously closes in 78% of preterm infant prior to hospital discharge. As does Hallman et al, he notes that there exists controversy about the significance, need for evaluation and management of the PDA in very preterm infants that results in substantial heterogeneity in clinical practice. He focuses on the need for further studies assessing the increased risks of prolonged patency and adverse outcomes by stating: “Without clear demonstration at adverse outcomes can be averted by medical or surgical closure of the ductus, the hypothesis that ductal patency is causal with respect to those outcome measures remains unproven.” and there is lack of evidence that necessitates equipoise regarding treatment options.” In their comprehensive review rich with informational Figures demonstrating anatomic, molecular and pharmacologic closure mechanism, Hallman et al carefully reviewed development of the PDA and its closure, prostaglandin synthesis and their inhibition, and pharmacodynamics of various drugs used of pharmacologic closure