Patent ductus arteriosus (PDA) is one of the most common congenital heart defects, accounting for 5%–10% of all congenital heart disease in term infants. The occurrence of PDA is inversely related to gestational age and weight, with an even greater incidence in preterm infants. The maintenance of ductal patency is essential for the normal development of the fetus. In the neonate, however, persistent patency of the ductus arteriosus (DA) is associated with significant morbidity and mortality. Normally, at birth, the DA constricts, resulting in intraluminal ischemic hypoxia, which eventually leads to closure and remodeling of the ductus. PDA in term infants is usually associated with a functional defect, whereas in preterm infants it is associated with immaturity. Normal physiologic mechanisms contributing to closure - oxygen tension and decreased prostaglandins—are altered in prematurity. Clinical signs of ductal patency include murmur, tachycardia, bounding peripheral pulses, and congestive heart failure and associated symptoms. Symptoms are not always present; therefore, diagnostic imaging is critical if a PDA is suspected on clinical grounds. Three management strategies are currently available for PDA: fluid restriction and diuretics (as clinically appropriate), medical intervention, and surgical ligation. Pharmacologic closure can be achieved via administration of intravenous indomethacin or ibuprofen lysine. While both agents have shown similar efficacy, ibuprofen lysine has demonstrated an improved safety profile, particularly in terms of renal effects, compared to indomethacin.

When medical management is warranted for closure of a persistent patent ductus arteriosus (PDA) in premature infants, treatment with a cyclooxygenase (COX) inhibitor is indicated. Indomethacin, available since 1976, has been the conventional pharmacologic treatment for PDA, but its use is associated with vasoconstrictive effects that impair renal, mesenteric and cerebral blood flow. Intravenous (IV) ibuprofen lysine, approved in the United States in 2006, has less severe vasoconstrictive effects on these vital organs than IV indomethacin. Clinical trials have shown both of these COX inhibitors to be equally effective in closing the PDA in approximately 70%–80% of treated infants, with less vasoconstrictive and adverse renal effects occurring with IV ibuprofen lysine.12 Several clinical considerations are important in the process of medical decision-making when faced with the need for PDA treatment with one of these pharmacologic agents in the premature infant. This paper focuses on these clinical considerations, including cerebral, renal and mesenteric blood flow, renal function, pulmonary effects, protein-binding capacity as it relates to hyperbilirubinemia, and platelet aggregation. No differences in chronic lung disease, pulmonary hypertension, hyperbilirubinemia and coagulopathy were observed in clinical trials when comparing these 2 COX inhibitors; however, significant differences have been observed in arterial blood flow to the cerebral, renal and mesenteric organs, suggesting that IV ibuprofen lysine may be the more favorable agent.

Patent ductus arteriosus (PDA) is a common complication in preterm infants. An intravenous (IV) cyclooxygenase (COX) inhibitor is the pharmacotherapy of choice. Concerns over adverse effects associated with the traditional treatment, IV indomethacin, have led to the investigation of other COX inhibitors to assist closure of PDA. IV ibuprofen lysine is a COX inhibitor that demonstrates similar efficacy to indomethacin with few adverse effects. In addition, IV ibuprofen lysine does not cause reductions in cerebral, renal, and mesenteric blood flow that can be seen with indomethacin, and thus ibuprofen therapy is not associated with reduced renal function. Ibuprofen is primarily metabolized by cytochrome P450 (CYP) 2C9. The immaturity of neonatal biotransformation pathways has a pronounced effect on the pharmacokinetic parameters of ibuprofen, particularly because CYP2C9 enzyme activity is known to be very low at birth and to increase rapidly over the first several days of life. Ibuprofen is highly bound to albumin, raising concern that ibuprofen may displace bilirubin and subsequently increase free bilirubin concentrations. However, the ibuprofen concentrations achieved with approved dosing with IV ibuprofen lysine are lower than those expected to result in displacement of bilirubin and related adverse effects. Factors such as gestational age and CYP2C9 polymorphism may affect ibuprofen metabolism and therefore optimal dosing, but further clinical investigation is needed in these areas. Other areas for future investigation include prolonged dosing regimens, prophylactic administration, and alternate indications. At the approved dose, IV ibuprofen lysine is a safe, effective pharmacologic agent to promote closure of PDAs in preterm infants.

Patent ductus arteriosus (PDA) is the failure of the ductus that arises from the distal dorsal aortic arch to close during the first few days of life. The treatment options for PDA include “watchful waiting,” pharmacologic therapy with cyclooxygenase (COX) inhibitors (COX-1 and COX-2), such as indomethacin or intravenous (IV) ibuprofen lysine, and surgery when medical interventions have proved ineffective. The clinical trials evaluating the utilization of IV ibuprofen lysine focus on either preventing the persistence of a PDA or treating the PDA in premature infants in whom the ductus does not close within 48 hours of birth. Although the role of COX inhibitors in prophylaxis of PDA has been studied, it has not been clearly delineated. Treatment of PDA in preterm low birth weight infants from the second day of life on with IV ibuprofen lysine has been studied in 4 major and 3 smaller clinical trials. Overall, in 7 studies with 492 patients, the closure rate of PDA was 75.1% with IV ibuprofen lysine compared to 73.5% with indomethacin. In addition, neonates treated with IV ibuprofen lysine had significantly better creatinine clearance, urine output, serum creatinine, and blood urea nitrogen (BUN) profiles than indomethacin-treated patients. Overall, IV ibuprofen lysine is as effective as indomethacin for closure of PDA, yet is associated with a better safety profile with fewer negative side effects when compared to indomethacin.

Management of neonatal patent ductus arteriosus (PDA) often is resource-intensive and costly. Therefore, it is in hospitals' best interests to ensure the most cost-efficient use of associated resources. Clinical status, comorbidities, and response to prior therapy are considered in selecting the most appropriate intervention for PDA management. Currently, supportive measures (e.g., fluid restriction), surgical ligation, and pharmacologically based medical therapy are the primary treatment modalities for correcting PDA. Medical therapy, which comprises a small percentage (2.0%–5.0%)1 of overall PDA treatment expenses in the United States, consists of either of the 2 intravenous (IV) cyclooxygenase (COX) inhibitors: IV indomethacin and the newly available IV ibuprofen lysine. Although IV COX inhibitors represent a small portion of medical expenses, their benefits appear to be considerable. Pharmacoeconomic studies have evaluated indomethacin's beneficial impact on cost-effectiveness per quality-adjusted life year in PDA prophylaxis; however, no analysis to date prospectively assesses the effect of COX inhibitors on resource use or expenses in treating PDA. Such analysis is desirable and should consider efficacy and safety outcomes, impact on health care resource use and length of stay (LOS), and any differential effects of the agents' safety profiles; notably, IV indomethacin adversely affects renal and mesenteric blood flow and increases serum creatinine and oliguria significantly more than IV ibuprofen. These observations lay the foundation to conduct studies assessing the influence of these differences on resource use, LOS and expenses associated with PDA management.

Cyclooxygenase inhibitors have proven efficacy in the treatment of patent ductus arteriosus (PDA). Intravenous indomethacin has been the only approved treatment for PDA available in the United States for the past 20 years. The armamentarium has recently been expanded with the approval of intravenous ibuprofen lysine in 2006. Ibuprofen lysine has been used for years in Europe, and the author reviews the extensive published literature. This review addresses common questions about ibuprofen lysine, summarizes the available literature, and discusses the data submitted to the Food and Drug Administration (FDA) in support of its approval. Three major trials served as the approval basis for the safety and efficacy of ibuprofen lysine. The author has summarized these studies and, where appropriate, presents pooled results from additional analyses that have not been previously published. Many practical questions regarding the drug, including dosing, administration, and storage are addressed. The results of recently completed but unpublished tests on stability and compatibility with commonly used drugs in the neonatal setting are also reviewed. Ibuprofen lysine now represents an alternative pharmacological option to surgery for the treatment of PDA.