Ibuprofen in the treatment of neonatal PDA

Patent ductus arteriosus (PDA) is a congenital cardiac defect that is characterised by the abnormal persistence of the ductus arteriosus post-natally. It is inversely proportional to gestational age, with 60% of babies born at less than 28 weeks gestation affected.1 30% of these ducts will spontaneously close in the first seven days of life, however persistent PDA is associated with mortality and morbidity, including a higher incidence of necrotising enterocolitis (NEC) and prolonged ventilator requirements.¹ There is significant variation in the severity of PDAs and the important relationship when considering when to treat PDA is birth weight. 60% of PDAs will close spontaneously in infants with a birth weight of 1001–1250g compared with only 42% in those infants between 500–750g.² There is some controversy among neonatologists about when and how to treat a PDA and this paper does not intend to address those.³

The importance of prostaglandin in the manipulation of the ductus arteriosus has been known since the 1970s with Elliott and Starling demonstrating the impact of PgE2 and oxygen on the duct in bovine foetal tissue⁴ and subsequently reporting administration of intravenous prostaglandin E1 to human infants with duct dependent circulations in 1975⁴ with improvement in arterial saturation. The first studies of a non-steroidal anti-inflammatory drug (NSAID) (indometacin) to close cardiovascularly unstable PDAs in preterm infants were also reported in the 1970s. Subsequent formal studies demonstrated the efficacy of indometacin for this indication.

The mechanism of action of NSAIDs in the closure of the PDA is through COX-mediated inhibition of prostaglandin production. Prostaglandins induce smooth muscle relaxation. Antagonising prostaglandin synthesis through COX-mediated inhibition results in vasoconstriction and causes the PDA to close.  NSAID-induced closure of the PDA is reported as being around 75–80% effective. However, with indometacin it is observed that this vasoconstriction reduces cerebral blood flow and reversible and irreversible renal impairment has been reported.

The first use of ibuprofen was reported by Vavarigou et al in 1996⁵ and followed up with a formal clinical study by van Overmeire in 1997.⁶  Ibuprofen and indometacin are both potent inhibitors of prostaglandin production, but ibuprofen has been found to have a more favourable safety profile (Table 1).

This difference in adverse effects is related to ibuprofen’s more selective inhibition of COX-2 over COX-1. Indometacin, being a less selective inhibitor, is thus pharmacologically more likely to cause COX-1 associated adverse effects (bleeding, renal impairment).

A meta-analysis of nine clinical trials in 2005⁹ comparing ibuprofen with indometacin for the medical closure of PDA in all infants found no significant efficacy difference between indometacin and ibuprofen (RR1.02, p=0.7) but there was a statistically significant benefit in urine output and serum creatinine with ibuprofen confirming that ibuprofen has less vasoconstrictive side effects affecting renal function. A systematic review by Ohlsson and colleagues¹⁰ found that ibuprofen is as effective as indometacin in the treatment of PDA, but has fewer side effects and actually confers protection to the infant from NEC.

Thus ibuprofen is recommended as the treatment of choice and medical management of haemodynamically significant PDAs with ibuprofen in preterm, low birth weight infants is now the first line treatment because of its improved safety profile.

Ibuprofen for the treatment of PDA in preterm infants is granted an orphan drug designation in the United States and Europe. It is important to note that there are two salts of ibuprofen used for closure of PDA: ibuprofen with trometamol in Europe (Pedea®, Orphan Europe) and ibuprofen lysine in the USA (Neoprofen®, Recordati Rare Diseases). In systematic reviews and meta-analysis the salt is not distinguished and the two forms are considered equivalent. This paper will focus on Pedea®.

Pedea® is licenced for up to two courses in infants under 34 weeks gestation given not earlier than after six hours of life. The timing of administration is important for early successful medical closure. Van der Lugt¹¹ reported that commencement of therapy after five days of life correlated with treatment failure and the need for a second course of therapy (76.1% success if intervention before five days of age compared with 60.5% if intervention after five days of age, p=0.036). If the ductus hasn’t closed 48 hours after completion of the first course of therapy, then a second course may be administered.  More than 80% of PDAs will close after two courses of parenteral ibuprofen therapy.¹²

Pedea® is formulated as a ready-to-use solution of 5mg/ml in 2ml ampoules. It is indicated for the treatment of haemodynamically significant PDA in preterm infants of less than 34 weeks gestation. It is administered as a single dose of 10mg/kg with two subsequent doses of 5mg/kg given every 24 hours. It is formulated specifically for administration to neonates and has an osmolality of 260–310mOsm/l to match the osmolality of neonatal plasma. Thus the solution does not require dilution prior to administration and can be infused neat over 15 minutes.⁷ However, the volumes required can be inappropriate for administration through programmable infusion pumps especially in low birth weight infants, therefore it can be diluted with 5% glucose or 0.9% sodium chloride to a volume that is convenient for administration via a syringe driver (usually 2–5ml total volume) but should still be administered over 15 minutes. It can go peripherally or centrally. There is no available data on physicochemical compatibility with other medicinal products.

Oral ibuprofen appears to be as effective in the treatment of PDA as parenteral ibuprofen¹³ however, oral therapy in pre-term and low birth weight infants carries its own risks. Oral suspensions are not formulated for the neonatal gastrointestinal tract and a number of them are hypertonic.¹⁴ Hypertonic solutions have been associated with NEC and intestinal perforation. Ibuprofen suspension has an osmolality of approximately 2000–4000mOsm/l¹⁵ and until there have been robust clinical studies to rule out the contribution hyperosmolar ibuprofen suspension makes to the incidence of NEC in infants with PDA then it cannot be recommended as first line therapy over parenteral therapy.

There is some concern about the protein binding characteristics of ibuprofen and displacement of bilirubin has been observed in vitro¹⁶ but this has not been observed in clinical practice. A study by Desfrere and colleagues including 34 preterm infants (less than 32 weeks) found that three therapeutic doses of ibuprofen had no effect on total bilirubin, unbound bilirubin and albumin binding affinity in infants with a serum bilirubin of <8.8mg/dl. The authors recommended caution in those patients with a bilirubin >8.8g/dl (150μmol/l).¹⁷ The link between ibuprofen and hyperbilirubinaemic encephalopathy is not proven, but caution should be exercised in the neonate with raised bilirubin. However in the presence of a haemodynamically significant PDA a risk-benefit assessment needs to be made taking into account the small risk of kernicterus with the relative risks to the infant of cardiovascular compromise and the alternative closure technique (surgical ligation).

Conclusions

PDA is a common problem experienced by pre-term neonates and is associated with significant morbidity and mortality. Prophylaxis of PDA in neonates is not recommended and medical intervention in the haemodynamically unstable infant is preferred. Ibuprofen has come to replace indometacin for medical treatment as it has a lower incidence of renal (oliguria, raised creatinine) and gastrointestinal (NEC and intestinal perforation) side effects than indometacin. This is because ibuprofen is a more selective inhibitor of COX-2 than indometacin so is not associated with the systemic side effects associated with COX-1 mediated vasoconstriction. It may even confer protection on the neonate against NEC.

Pedea® is the only preparation of ibuprofen licenced for PDA closure available in Europe and is administered as three doses over three days. It is formulated in a ready to use solution to reduce the risk of medication error and therefore it would usually be administered neat but may be diluted for convenience with 0.9% sodium chloride or 5% glucose. There is no requirement for in-line filtration. Despite ibuprofen’s protein binding characteristics there has been no demonstrated episode of hyperbilirubinaemia or encephalopathy that can be attributed directly to ibuprofen therapy for PDA closure, but caution should be exercised when serum bilirubin levels are greater than 8.8g/dl.