Patent ductus arteriosus (PDA) is one of the most common clinical findings in preterm infants.1 Patent ductus arteriosus occurs when the ductus arteriosus fails to close following birth and is most often found in the setting of prematurity, affecting approximately 50% of all preterm infants. Patent ductus arteriosus with significant left-to-right shunts have been associated with increased morbidity in preterm infants for more than 50 years.2 Hemodynamically significant PDAs cause decreased renal blood flow, intestinal ischemia, and decreased cerebral artery blood flow.3-6 In addition, PDAs produce high pulmonary blood flow, often in the setting of surfactant deficiency and increased capillary permeability, which results in pulmonary edema and increased ventilation requirements.7 In extremely preterm infants, these alterations in vital organ blood flow may increase the risk of necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, and chronic lung disease (CLD).8-11 These morbidities are common complications of preterm birth and a causative link to PDA has not been proven.

Care of the preterm infant with PDA in the neonatal intensive care unit is an ongoing challenge. Little consensus regarding treatment of PDA currently exists.12 Treatment requires careful consideration of the risks and benefits of available therapies, namely, surgical ligation and pharmacological interventions. While surgery typically results in reliable closure of the PDA, it is also associated with both short- and long-term surgical complications including infection and neurodevelopmental impairment. For this reason, surgical ligation of the PDA is usually considered only after medical treatment, which is focused primarily on a pharmacological approach to closing the PDA. Here, I briefly review both the intravenous (IV) and enteral administration of medications to closing PDA in the preterm infants.

PHARMACOLOGIC APPROACH TO CLOSING THE PDA: IV ADMINISTRATION OF MEDICATIONS

Prophylactic use of IV indomethacin in extremely preterm infants within the first 24 hours of life has been hypothesized to improve outcomes by decreasing associated comorbidities in a population commonly afflicted with PDA.13 A meta-analysis of 19 randomized controlled trials including 2872 infants demonstrated that prophylactic IV indomethacin reduces the incidence of symptomatic PDA (relative risk: 0.44, 95% confidence interval: 0.38-0.50; number needed to treat = 4) and decreases the rate of surgical ligation (relative risk: 0.51, 95% confidence interval: 0.37-0.71; number needed to treat = 20).14 Indomethacin also reduces the risk of pulmonary hemorrhage in the first week of life.15 Despite a significant reduction in symptomatic PDA and pulmonary hemorrhage, no differences were detected in short-term morbidities including CLD. However, the most compelling indication for prophylactic indomethacin is the prevention of severe intraventricular hemorrhage (grade 3 or 4), which may occur as a result of reduction in early ductal shunting.16 Adverse effects of indomethacin have been shown to include the need for supplemental oxygen during treatment and decreased urine output.

Intravenous ibuprofen represents an alternative therapy to indomethacin. However, IV ibuprofen does not prevent severe intraventricular hemorrhage and also has concerning adverse effects, including bilirubin displacement and the potential to increase the risk of CLD. Intravenous ibuprofen has been compared with IV indomethacin for the treatment of PDA in 11 randomized controlled trials including 643 neonates. Trials consistently demonstrate equivalent efficacy for PDA closure, with ibuprofen having less impact on urine output and serum creatinine.17 Despite differing impacts on mesenteric blood flow, the incidence of necrotizing enterocolitis has not been shown to differ between the 2 medications.17 Concern exists regarding the pulmonary outcomes of neonates treated with ibuprofen. Ibuprofen-treated patients have an increased incidence of CLD compared with those treated with indomethacin (relative risk: 1.28, 95% confidence interval: 1.03-1.60; number needed to treat = 12).17 There is currently a lack of studies examining the long-term outcome of neonates treated with ibuprofen. Overall, the advantages of ibuprofen with regard to renal function do not appear to justify the potential risks associated with increasing CLD, given that efficacy in treating the PDA has not been shown to differ following administration of ibuprofen and indomethacin.

PHARMACOLOGIC APPROACH TO CLOSING THE PDA: ENTERAL ADMINISTRATION OF MEDICATIONS

Given the high cost of more than $350 per vial for IV indomethacin and ibuprofen and the sporadic availability of IV medications, enteral administration of medications is important to consider.18,19 Enteral administration of ibuprofen has been evaluated in 7 small randomized trials including 189 neonates, showing similar efficacy to IV indomethacin. Three trials including 236 neonates showed superior efficacy compared with IV ibuprofen, which may be explained by pharmacokinetic differences between enteral and IV routes.20 Enteral administration results in lower peak levels but longer time to elimination and higher overall exposure.21 Of note, studies of enteral ibuprofen administration show an increased incidence of gastrointestinal (GI) bleeding and spontaneous intestinal perforation when compared with placebo.22,23 This adverse effect may be explained by the high osmolarity of enteral ibuprofen administered in the setting of mesenteric blood flow impairment associated with the PDA.24 Future studies of enteral ibuprofen must carefully monitor for this GI-related adverse effect. Based on the current state of the evidence, enteral ibuprofen should be reserved for times when availability of IV products is limited or in clinical cases when IV access is especially problematic for the preterm infant.

Administration of acetaminophen is an attractive alternative for PDA closure due to wide availability, low cost, and a safety profile that exceeds the other medications currently available. The efficacy of this drug in the preterm infant was first proposed in 2011 on the basis of an incidental finding of PDA closure in a preterm infant, given acetaminophen for an unrelated indication.25 To date, 12 case series including 88 patients describe enteral or IV acetaminophen treatment of PDA in patients who either failed or who had contraindications to COX inhibitors, such as recent intracranial hemorrhage, renal failure, or active corticosteroid therapy.26 Clinical success, with definitions ranging from requiring no further therapy to documented PDA closure, is reported in 67 of 88 patients (76%). Two randomized controlled trials (n = 240) have demonstrated the equivalent efficacy of enteral acetaminophen with enteral ibuprofen for the treatment of PDA.27,28 Adverse events were rare with either therapy, with 1 trial noting increased GI bleeding in patients treated with ibuprofen.

Existing case series and clinical trials of acetaminophen for PDA closure most commonly utilize 15 mg/kg/dose every 6 hours for 3 to 6 days. This dosing is considerably higher than that required to achieve target concentrations for pain or fever (~10 mg/L).29,30 Whether this aggressive dosing approach supports observations of efficacy or puts neonates at unnecessary risk for toxicity is unknown. The relative efficacy and safety of enteral versus IV acetaminophen has not been studied. Like enteral ibuprofen, enteral acetaminophen has a high osmolarity. Therefore, IV acetaminophen, if available, should be utilized in patients on low-volume enteral feedings to minimize the risk of GI bleeding or perforation. Acetaminophen appears to be an exciting alternative therapy for PDA, but more information is needed regarding this approach to caring for the preterm infant with PDA. Ongoing studies focused on the mechanism of action, efficacy, safety, and optimal dose for this novel use of acetaminophen are required.

CONCLUSION

Patent ductus arteriosus remains a common occurrence among preterm infants cared for in the neonatal intensive care unit. Ideally, PDA can be treated medically, thereby avoiding the need for surgical ligation. Historically, medical treatment has most often involved IV administration of indomethacin or ibuprofen. Given the cost and availability of IV pharmaceuticals for preterm infants, studies have evaluated the enteral administration of ibuprofen and more recently, acetaminophen. Enteral ibuprofen has been shown to be effective in treating the PDA. However, the therapeutic effect of enteral ibuprofen administration must be balanced against adverse side effects including GI bleeding and intestinal injury (ie, spontaneous intestinal perforation). Enteral administration of acetaminophen has recently been shown to be equally effective in treating the PDA with fewer side effects. While more studies are needed, use of enteral acetaminophen is a potentially exciting new approach to pharmacologic treatment of PDA in preterm infants.

-Katherine E. Gregory, PhD, RN

Senior Nurse Scientist

Department of Pediatric Newborn Medicine

Department of Nursing

Brigham and Women's Hospital

Boston, Massachusetts

References