Ibubrofen in the Treatment of Patent Ductus Arteriosus in Preterm Infants: What We Know, What We Still Do Not Know

Abstract

The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely cause of mortality and morbidity, including broncho-pulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, retinopathy of prematurity. The incidence of patent ductus arteriosus is inversely proportional to gestational age and infants with the lowest gestational ages are the most exposed to the complications of prematurity. So, associations between patent ductus arteriosus and the other morbidities may not be causative and patent ductus arteriosus could be more a sign of immaturity and severity of disease than the cause of these problems. Non-steroidal anti-inflammatory agents, such as indomethacin or ibuprofen, have been shown to be effective in closing or preventing patent ductus arteriosus, with differences in side effects. However nearly all randomized controlled trials have been designed with the closure of the ductus arteriosus, not mortality or morbidity, as the main endpoint. Thus, evidence is still lacking on the eventual benefits for the patient of pharmacological or surgical intervention on PDA. Moreover, both ibuprofen and indomethacin efficacy seems markedly reduced in extremely low gestational age infants, who are the most likely to benefit from such intervention. The explanation of the reduced pharmacodymanic effect in such population is unclear; so far, studies using increased dosing of ibuprofen have failed to show a clear benefit. Prophylaxis with indomethacin or ibuprofen has failed to show sustained benefits on neurodevelopment at 2 years of age in low gestational age infants. New curative trials may aim at investigating the effects of early curative administration of ibuprofen, which has reduced side effects compared to indomethacin, on immature kidney function, on mortality and morbidity in very low gestational age infants, ideally with a combined endpoint such as survival in the absence of severe neurodevelopmental alteration at 2 years age. Despite an understandable reluctance given the historical background of systematic, therapeutic closure of ductus arteriosus in preterm infants, there are no definite ethical obstacles to a placebo-controlled design.

Bedside Surgery to Treat Patent Ductus Arteriosus in Low-Birth-Weight Premature Infants

“…The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely cause of mortality and morbidity, including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and ROP. 6 Prostaglandin E2 has the opposite effect to that of oxygen; it relaxes smooth muscle and tends to inhibit the closure of the ductus arteriosus. Non-steroidal anti-inflammatory agents, such as indomethacin or ibuprofen, have been shown to be effective in closing or preventing PDA, with differences in side effects.…”

“…The major factor closing the ductus arteriosus is the tension of oxygen, which increases significantly after birth. The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely cause of mortality and morbidity, including broncho-pulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and ROP 6…”

Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants

“…As a result, emphasis has been placed on targeted pharmacotherapeutic treatment of PDAs when deemed hemodynamically significant by the clinician based on clinical and echocardiographic parameters . However, lack of pharmacokinetic and pharmacodynamic data on nonsteroidal anti-inflammatory drug use in preterm infants has led to the use of different drugs in varying doses and routes of administration . The 2 most commonly used treatment options are standard doses of intravenous ibuprofen and intravenous indomethacin …”

“…However, lack of pharmacokinetic and pharmacodynamic data on nonsteroidal anti-inflammatory drug use in preterm infants has led to the use of different drugs in varying doses and routes of administration . The 2 most commonly used treatment options are standard doses of intravenous ibuprofen and intravenous indomethacin …”

Compatibility of intravenous ibuprofen with lipids and parenteral nutrition, for use as a continuous infusion

“…Pharmacological treatment consists of using non-steroidal anti-inflammatory drugs (NSAIDS), typically Indomethacin or Ibuprofen. There is an ongoing debate about which of the two NSAIDS is best suited for this intervention [ 2 ]. A Cochrane review published in 2015 suggested Ibuprofen to be as effective as indomethacin in closure efficacy but with reduced renal and gastric complications, thereby making it an agent of choice in many neonatal units [ 3 ].…”