Comparative tolerability of pharmacological treatments for patent ductus arteriosus

The ductus arteriosus is a vascular channel which, although vital to the fe tal circulation, rapidly becomes unnecessary and even deleterious after bir th. As such, it is 'preprogrammed' to constrict within the first few hours of life. In infants born prematurely this natural closure is often delayed and/or ineffective. In this review, we summarise the current knowledge of t he delicately orchestrated control of normal ductal closure, with emphasis on the role of various biochemical mediators. The major focus of this review, however, is on pharmacological approaches d esigned to prevent and/or treat the persistently patent ductus arteriosus ( PDA) which often fails to constrict spontaneously in the premature infant. The standard treatment regimen is based on the administration of 3 doses of the nonselective cyclo-oxygenase inhibitor, indomethacin. We begin by exam ining, from the vantage point of the ductus, the use of this indomethacin a s a tocolytic. It seems that antenatal administration of indomethacin can c ause transient, reversible ductus constriction which renders the post-treat ment ductus resistant to subsequent closure, both natural and therapeutic. We then review some of the pros and cons associated with the prophylactic a dministration of indomethacin. Although prophylactic indomethacin is aimed primarily at preventing intraventricular haemorrhages in premature neonates , it does tend to reduce the risk of PDA as well. We then describe some novel therapeutic approaches to effect ductal closure with indomethacin, including the use of continuous infusions to minimise t oxic vasoconstrictive phenomena and the use of prolonged maintenance dose t o prevent PDA recurrences. Finally we discuss some of the newer agents described more recently which p lay a role in closing the persistently patent ductus over tile next decade. Most prominent of these is ibuprofen which some studies have shown to have less undesirable vasoconstrictive adverse effects. Studies which compare t he use of ibuprofen to indomethacin are summarised.