Therapeutic manipulation of the ductus arteriosus: current options and future prospects

Abstract

The ductus arteriosus is a large fetal vessel connecting the pulmonary artery with the aorta and allowing right ventricular blood to bypass the unexpanded lungs. At birth, with the start of lung ventilation and the attendant rise in blood oxygen tension, the ductus closes and the cardiovascular system acquires its final arrangement. However, in the prematurely born infant, this shunt may remain patent (patent ductus arteriosus -PDA) with adverse consequences on hemodynamic homeostasis. Conversely, there are cardiac malformations in which patency of the duct is required to maintain the pulmonary or systemic circulation prior to corrective surgery. Based on the notion that patency is an active process sustained primarily by prostaglandin (PG) E 2 , PDA is currently managed with synthesis inhibitors, indomethacin or ibuprofen, while any necessary persistence of the duct after birth is achieved with the infusion of PGE 1 . However, the former procedure presents a relatively high incidence of failures for the likely combination of the 2 events: the relaxing influence of the agents compensating for the loss of PGE 2 and the immaturity of the oxygen-triggered contractile mechanism. On the other hand, PGE 1 treatment loses some of its efficacy with time and may also be complicated by troublesome side effects. This article presents possible new approaches to therapy still based on the manipulation of the relaxing mechanism(s) responsible for duct patency. At the same time, however, the idea is put forward that the management of these sick infants may find its definitive solution only with tools being designed on the operation of the oxygen-sensing/effector system. REVIEW ARTICLE Therapeutic manipulation of the ductus arteriosus: current options and future prospects 59The role of PGE 2 has also become increasingly complex with the realization that its action within the ductus is not limited to muscle relaxation. In brief, it has been shown that PGE 2 also contributes to closure of the duct, antenatally by promoting the formation of intimal cushions, 18,19 which are critical for the sealing of the lumen, and postnatally by being involved in remodeling of the vessel wall, 18,19 that is, in the process leading to structural closure and, ultimately, to the demise of the shunt. In essence, one is dealing with an agent exerting opposite effects, definitely different in their time course but still capable to introduce some degree of unpredictability in the response to a synthesis inhibitor. In addition, over the years, the synthetic system for PGE 2 has revealed its full complexity, first with the identification of 2 isoforms, COX-1 and COX-2, in what was originally perceived as a single entity, and second, with the characterization of terminal enzymes in the synthetic cascade (i.e., the PGE synthases). The ductus is endowed with a complete, COX and PGE synthase, system, 15 hence making it unrewarding to attempt to replace currently used nonselective inhibitors with the newly developed COX-2 inhibitors. Conversely, as di...

Outcome Transcatether Patent Ductus Arteriosus Closure in Children

“…Left ventricular volume overload is often seen in PDA and appears to be necessary to increase cardiac output by responding to the Frank Starling mechanism circulation (14) . Closure of the PDA will result in loss of the aortic to pulmonary shunt resulting in a decrease in left ventricular preload.…”

Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment

“…Although catheter-based closure is also an option, its usefulness is limited by the technical challenges of implanting devices in very preterm infants [77,78]. Conversely, certain congenital heart defects require that the DA remain patent via prostaglandin infusion or stent implantation in order to maintain life-saving pulmonary or systemic circulation prior to corrective surgery [79,80]. However, adverse effects including peripheral vasodilation and apnea have been associated with infusion of PGE 1 [81].…”