Non-steroidal anti-inflammatory drugs (NSAIDs) in the management of patent ductus arteriosus (PDA) in preterm infants and variations in attitude in clinical practice: a flight around the world

The primary objective of this review is to verify if there are differences in the diagnostic and therapeutic strategies in cases of PDA employed in different NICUs that might help explain the different percentages of duct closure, surgical ligation and outcome in these vulnerable patients. The secondary objective is to document if the selection of a specific NSAID and/or the way of administration are based on factors such as costs and local availability of drugs, as well as influenced by clinical and haemodynamic parameters, potential risks, local experience and the existing literature. Data Sources were MEDLINE, EMBASE, Cochrane Library and analysis of the most important papers were performed. We examined a total of 89 trials including 15,657 neonates (with gestational ages between 22 and 35 weeks and study weights between 380 and 2500 g), due to the lack of homogeneity of case studies it was not possible to standardize for gestational age and weight. To simplify, the studies we considered were subdivided into 5 groups corresponding to 5 tables: 1- INDO-prophylaxis (15 trials); 2- IBU-prophylaxis (11 trials); 3- INDO-therapy (18 trials); 4- IBU-therapy (16 trials); 5- IBU vs INDO therapy (29 trials). Each table reports the journal, the author and year, the type of study, the number of neonates enrolled, the drugs used, management after failure of the first cycle, percentage of duct closure and adverse effects. Treatment with indometacin is prescribed prevalently in the United States and Canada. According to the data collected, prolonged treatment and administration of high doses would appear to be more effective. The early administration of indometacin has been associated with gastrointestinal bleeding, renal insufficiency, altered cerebral self-regulation and, especially when administered together with postnatal steroids, it has been correlated with isolated intestinal perforation. Ibuprofen treatment is preferred in Europe but it may be associated with nephrotoxicity and an increase in BDP and ROP, although less frequently compared to indometacin. Indometacin is associated with major nephrotoxicity, as well as with a higher incidence of NEC, intestinal perforations and a reduced cerebral blood flow. Despite this, the administration of ibuprofen does not appear to be without short- and long-term renal adverse effects.