Authors: Harlan Husted, Pharm.D, BCPS; Deborah Raithel, Pharm.D, BCPS
Editors: Susan Butler, Pharm.D, Kyle Gunter, Pharm.D, BCPS, Sandra Hennessy, Pharm.D, Christopher McPherson, Pharm.D, Nicole Passerrello, Pharm.D, BCPS, Christine Robinson, Pharm.D, Eloise Woodruff, Pharm.D, and Joanna Wrobel, Pharm.D
The patent ductus arteriosus (PDA) is a significant remnant of fetal circulation which may contribute to common morbidities in premature infants.1-3 While the presence of the ductus arteriosus is necessary for the fetus, serving as a pathway for oxygenated blood from the placenta to bypass the lungs and enter the systemic circulation, it can cause significant harm if it remains open in the infant. Continued shunting of blood back to the pulmonary artery from the aorta can lead to chronic lung disease, heart failure, and necrotizing enterocolitis (NEC).
Functional closure of the ductus arteriosus is achieved through dynamic changes in the ductal lumen via a reduction in prostaglandin E2 (PGE-2)-mediated processes, ultimately resulting in ductal constriction and subsequent anatomical remodeling.1-3 In healthy late preterm and term infants, this process is generally completed shortly after birth, resulting in a separation of the pulmonary and systemic circulatory systems. The ductus arteriosus is considered persistently patent if it remains open beyond 72 hours of life. A persistent PDA occurs most often in premature infants where closure can take significantly longer, if it occurs at all, and is further complicated by the reduced functional capacities of the cardiac, pulmonary, and renal systems due to developmental immaturity.
For premature infants, ductal closure may require assistance via pharmacological management and/or surgical ligation. Extremely low birth weight infants require intervention up to 70% of the time.1 Surgical ligation may be considered in infants with an inadequate response to pharmacologic therapy; however, the risks versus benefits must be weighed as data has shown an increased risk of neurodevelopmental impairment in infants undergoing surgical ligation.4-5 Non-steroidal anti-inflammatory drugs (NSAIDs), specifically indomethacin and ibuprofen, have been the initial medications of choice for PDA closure.1-2,6-7 NSAIDs block PGE-2 production via inhibition of the cyclooxygenase (COX) enzymes, thereby facilitating thickening of the lumen with ductal closure. The success rate of NSAIDs for PDA closure is reported to be approximately 70-85%.
Ductal closure utilizing NSAIDs therapy is not without its own risks. Many of the adverse effects of NSAIDs are related to their vasoconstrictive effects on renal, cerebral, and mesenteric vessels.1-2 Clinical trials have shown that the effects are greater with indomethacin compared to ibuprofen. Because of this, indomethacin has the potential to reduce the incidence of intraventricular hemorrhage, but this is offset by an increased risk of oliguria and renal failure. Gastrointestinal adverse effects, such as spontaneous intestinal perforation, gastrointestinal bleeding, and NEC, have been shown to have either a similar incidence or conflicting results when comparing agents. NSAIDs can also inhibit platelet aggregation leading to an increased risk of bleeding, although this effect tends to persist longer with indomethacin. A unique effect of ibuprofen is interference with the binding of bilirubin to albumin, potentially leading to hyperbilirubinemia. Additionally, the United States has seen dramatically increased costs of the intravenous formulations of these agents in recent years, which practitioners must also take into consideration when deciding to utilize these agents.8
While NSAIDs are known to inhibit COX activity via the arachidonic acid pathway, acetaminophen is thought to inhibit peroxidase activity in the same pathway, leading to downstream reduction of PGE-2. Acetaminophen started to gain interest in the neonatal population for PDA closure after Hammerman and colleagues published an initial case series in 2011.9 To date, there are 14 published case series detailing this method of PDA closure in infants.9-22 Reported gestational ages ranged from 23 to 37 weeks. Only one study by Yurturran and colleagues utilized acetaminophen as the initial course of therapy for PDA closure,22 while the remaining 13 case series only included patients who had either failed previous treatment with NSAIDs, had contraindications to NSAIDs, or were beyond 3 weeks postnatal age.9-21 The most common regimen used was acetaminophen 15 mg/kg/dose every 6 hours, with the intravenous formulation used in 6 case series and the enteral formulation used in 8 case series. The overall success rate of the 130 patients included was 79.2%, although the criteria used to define PDA closure varied between publications. Adverse effects included elevations in various liver function tests, which would be expected based on the toxicity profile of acetaminophen and the decreased ability to metabolize acetaminophen via glucuronidation in newborns; however this was only reported in 6 total patients. It should be noted that practitioners must be cautious when reviewing the results of the data as the likelihood of publication bias exists with case series and may skew the results. For example, two of the case series published reported success rates of ≤ 10% for PDA closure after treatment with intravenous acetaminophen, which is in contrast to the higher success rates from other case series.
Recently, two randomized controlled trials were published which now provide additional evidence when considering acetaminophen for PDA closure.23-24 Both studies were non-inferiority trials comparing enteral acetaminophen 15 mg/kg/dose every 6 hours for 3 days to enteral ibuprofen 10 mg/kg/dose followed by 5 mg/kg/dose at 24 and 48 hours. The first study was published by Oncel and colleagues and analyzed 80 preterm infants that successfully completed their treatment protocol.23 Demographics included a birth weight ≤ 1250 grams, gestational age ≤ 30 weeks, a postnatal age of 48-96 hours, and a significant PDA found on ECHO. After the first 3 days of treatment, PDA closure was found in 77.5% of the ibuprofen-treated infants and 72.5% of the acetaminophen-treated infants. Re-opening of the ductus arteriosus occurred in 16.1% of the ibuprofen-treated infants and 24.1% of the acetaminophen-treated infants. No statistically significant differences in adverse events were noted, with similar rates of sepsis, gastrointestinal bleeding, and NEC seen between groups. The second study was published by Dang and colleagues and included 138 preterm infants who completed the treatment protocol.24 Demographics included a gestational age ≤ 34 weeks, a postnatal age of ≤ 14 days, and a hemodynamically significant PDA found on ECHO. Overall PDA closure was found in 78.8% of the ibuprofen-treated infants and 81.2% of the acetaminophen-treated infants. Similar rates of ductal re-opening were again seen, with an occurrence of 9.5% in the ibuprofen-treated infants and 7.7% in the acetaminophen-treated infants. This study found a statistically significant increase in the rate of hyperbilirubinemia and gastrointestinal bleeding in the ibuprofen-treated infants compared to the acetaminophen-treated infants; however, no difference was noted in the rates of oliguria, renal failure, sepsis, or NEC. The results of both of these studies suggest that enteral acetaminophen is just as effective as enteral ibuprofen in the initial treatment of PDA in premature infants and may have an improved safety profile.
When determining which treatment modality is best for a given patient, many factors come into consideration. Would this patient benefit from pharmacological intervention or will the PDA potentially close on its own? Does this patient have any additional risk factors that would limit the use of a particular agent based on side effects, such as renal dysfunction or active bleeding? What products are available on your institution’s formulary for intravenous and oral use? Is the patient taking enteral feeds and does your institution allow feeding during the administration of NSAIDs? Has the patient received previous courses of NSAIDs or acetaminophen for PDA closure? All of these questions must be weighed on a case-by-case basis, although it would be recommended for individual institutions to begin developing their own treatment algorithms for the management of persistent PDA. At this time, acetaminophen seems to be a reasonable option for practitioners to consider for PDA closure, especially in those patients for which NSAIDs may be contraindicated.
- Corff KE, Sekar KC. Clinical considerations for the pharmacological management of patent ductus arteriosus with cyclooxygenase inhibitors in premature infants. J Pediatr Pharmacol Ther. 2007;12:147-57.
- Johnston PG, Gillam-Krakauer M, Fuller MP, and Reese J. Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit. Clin Perinatol. 2012;39: 111-36.
- Le J, Gales MA and Gales BJ. Acetaminophen for patent ductus arteriosus. Ann Pharmacother. 2015;49:241-6.
- Koehne PS, Bein G, et al. Patent ductus arteriosus in very low birthweight infants: complications of pharmacological and surgical treatment.” J Perinat Med. 2001;29:327-34.
- Weisz DE, More K, McNamara PJ, et al. PDA ligation and health outcomes: a meta-analysis. Pediatrics. 2014;133:e1024-46.
- Neumann R, Schulzke SM, and Buhrer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis.” Neonatology. 2012;102:9-15.
- Hammerman C, Bin-Nun, A, and Kaplan M. Managing the patent ductus arteriosus in the premature infant: a new look at what we thought we knew. Semin Perinatol. 2012;36:130-8.
- Jobe AH. Drug pricing in pediatrics: the egregious example of indomethacin. Pediatrics 2007; 119: 1197-8.
- Hammerman C, Bin-Nun A, Markovitch E, et al. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics. 2011;128:e1618-21.
- Alan S, Kahvecioglu D, Erdeve O, et al. Is paracetamol a useful treatment for ibuprofen-resistant patent ductus arteriosus? Neonatology. 2013;104:168-9.
- EL-Khuffash A, James AT, Cleary A, et al. Late medical therapy of patent ductus arteriosus using intravenous paracetamol. Arch Dis Child Fetal Neonatal Ed. 2015;F1-4.
- Jasani B, Kabra N, and Nanavati RN. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm infants. J Postgrad Med. 2013;59:312-4.
- Kessel I, Waisman D, Lavie-Nevo K, et al. Paracetamol effectiveness, safety and blood level monitoring during patent ductus arteriosus closure: a case series. J Matern Fetal Neonatal Med. 2014;27:1719-21.
- Nadir E, Kassem E, Foldi S, et al. Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol. 2014;34:748-9.
- Oncel MY, Yurttutan S, Degirmencioglu H, et al. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology. 2013;103:169.
- Oncel MY, Yurttutan S, Uras N, et al. An alternative drug (paracetamol) in the management of patent ductus arteriosus in ibuprofen-resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed. 2013;98:F94.
- Ozdemir OM, Dogan M, Kucuktasci K, et al. Paracetamol therapy for patent ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol. 2014;35:276-9.
- Roofhooft DWE, van Beynum IM, Helbing WA, et al. Paracetamol for ductus arteriosus closure: not always a success story. Neonatology. 2013;104:170.
- Sinha R, Negi V, and Dalal SS. An interesting observation of PDA closure with oral paracetamol in preterm infants. J Clin Neonatol. 2013;2:30-32.
- Tekgunduz KS, Ceviz N, Demirelli Y, et al. Intravenous paracetamol for patent ductus arteriosus in premature infants – a lower dose is also effective. Neonatology. 2013;104:6-7.
- Terrin G, Conte F, Scipione A, et al. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm infants. Ital J Pediatr. 2014;40:21-4.
- Yurttutan S, Oncel MY, Arayici S, et al. A different first-choice drug in the medical management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med. 2013;26:825-7.
- Oncel MY, Yurttutan S, Erdeve O, et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr. 2014;164:510-4.
- Dang D, Wang, D, Zhang C, et al. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLOS ONE. 2013;8:1-5.