Therapeutic closure of the ductus arteriosus: Benefits and limitations

Abstract

Patency of the ductus arteriosus (PDA), a common complication of preterm birth, has been associated to increased risk for intraventricular cerebral hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia and death. Consequently, prophylactic or curative treatment has been advocated before the critical left-to-right shunting occurs. A host of studies has shown that both pharmacological agents and surgical closure are effective in closing the ductus arteriosus in premature infants. Indomethacin has long been the drug of choice. However, renal and cerebral haemodynamic side effects have been frequently reported. Strategies to minimise adverse effects of indomethacin, such as the association with frusemide, dopamine or the use of low-dose prolonged treatment with indomethacin have failed or shown partial benefit. Other NSAIDs have been investigated. But either the profile of adverse effects was unfavourable, as in the case of mefenamic acid, or their efficacy was less than that of indomethacin for PDA closure. More recently, ibuprofen has been proposed for the treatment of PDA as it was shown to induce less adverse effects on cerebral blood flow, intestinal and renal hemodynamics, while retaining similar efficacy to indomethacin. However, since renal perfusion, GFR and diuresis in early neonatal life strongly depend on the vasodilator effects of PGs on the afferent glomerular arterioles, ibuprofen, as other COX-inhibitors may not be exempt of some renal undesirable effects. While numerous studies have shown that PDA is a risk factor associated with immaturity and with increased incidence of complications of preterm birth, including broncho-pulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis and death, there is little evidence that such association is causative. Moreover, still little evidence exists from even recent randomized controlled trials that the pharmacological closure of PDA benefits to premature infants in terms of clinically significant short-term or medium-term outcomes, beyond a positive effect on DA patency. The use of COX-inhibitors for the prophylaxis or closure of PDA during the first hours or days of life should thus be cautious and based on an individual evaluation of benefit and risk. There is need of a randomized, placebo-controlled trials designed to assess the benefits in terms of mortality and morbidity outcomes of an early, or even very early pharmacological closure of PDA in extremely low gestational age infants.

Population pharmacokinetic study of gentamicin in a large cohort of premature and term neonates

“…The small number of patients ( n = 27) might have limited the power to detect a true effect. It is also possible that confounding factors were reflected this way, since those newborns had a very low body weight, (mean 852 g, range 440–1390 g), as well as haemodynamically significant PDA, which is associated with poor renal perfusion . Even so, PDA had no significant impact on CL per se in this analysis.…”

Drug Closure of a Patent Ductus Arteriosus in An Extremely Low Birth Weight Premature Newborn. A Case Report

“…Low diastolic blood pressure values associated with the diastolic theft revealed by transfontanellar ultrasound in an extremely low birth weight premature newborn, without clinical evidence of ductal dependent cardiac malformation, raised the suspicion of a persistent ductus arteriosus. Taking into account the increased frequency of patent ductus arteriosus in extremely low birth weight premature newborns, as revealed by other studies [4,5], coupled with a respiratory tract infection, pathology common in infants with this malformation [4], initiation of cyclooxygenase inhibitor therapy was decided. Due to reduced renal side effects compared to other drugs, ibuprofen in three consecutive doses is administrated.…”

“…Patent ductus arteriosus is a common pathology in extremely low birth weight premature newborns, being identified in 80% of cases. This increases the risk of developing intraventricular haemorrhage, necrotic ulcerative enterocolitis, or chronic lung disease [5]. Clinical diagnosis of patent ductus arteriosus in the premature new-born weighing less than 1000 grams represents a challenge, given the association with respiratory distress syndrome by surfactant deficiency [3].…”

A Developmental Approach to Drug-induced Liver Injury in Newborns and Children

“…Due to these side effects of indomethacin, another cyclooxigenase inhibitor, a derivative of ibufenac, ibuprofen, emerged. A large number of randomized studies comparing the two drugs showed the same efficacy for the closure of the patent ductus aretriosus [162,163]. Moreover, the use of ibuprofen has demonstrated fewer side effects on the renal, mesenteric and cerebral blood flows [164].…”