Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants

Rheinlaender, Cornelia; Helfenstein, D.; Walch, E. W.; Berns, Monika; Obladen, Michael; Koehne, Petra

doi:10.1111/j.1651-2227.2008.01007.x

Cited by 36 publications

(21 citation statements)

References 20 publications

(26 reference statements)

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“…In addition, two in vivo studies have demonstrated that ibuprofen treatment results in higher peak levels of total serum bilirubin and longer durations of phototherapy. [31], [32].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Oral Paracetamol versus Ibuprofen in Premature Infants with Patent Ductus Arteriosus: A Randomized Controlled Trial

et al. 2013

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Trial DesignOral ibuprofen has demonstrated good effects on symptomatic patent ductus arteriosus (PDA) but with many contraindications and potential side-effects. In the past two years, oral paracetamol administration to several preterm infants with PDA has been reported. Here, a randomized, non-blinded, parallel-controlled and non-inferiority trial was designed to evaluate the efficacy and safety profiles of oral paracetamol to those of standard ibuprofen for PDA closure in premature infants.MethodsOne hundred and sixty infants (gestational age ≤34 weeks) with echocardiographically confirmed PDA were randomly assigned to receive either oral paracetamol (n = 80) or ibuprofen (n = 80). After the initial treatment course in both groups, the need for a second course was determined by echocardiographic evaluation. The main outcome was rate of ductal closure, and secondary outcomes were adverse effects and complications.ResultThe ductus was closed in 65 (81.2%) infants of the paracetamol group compared with 63 (78.8%) of the ibuprofen group. The 95% confidence interval of the difference between these groups was [−0.080,0.128], demonstrating that the effectiveness of paracetamol treatment was not inferior to that of ibuprofen. In fact, the incidence of hyperbilirubinemia or gastrointestinal bleeding in the paracetamol group was significantly lower than that of the ibuprofen group. No significant differences in other clinical side effects or complications were noted.ConclusionThis comparison of drug efficacy and safety profiles in premature infants with PDA revealed that oral paracetamol was comparable to ibuprofen in terms of the rate of ductal closure and even showed a decreased risk of hyperbilirubinemia or gastrointestinal bleeding. Therefore, paracetamol may be accepted as a first-line drug treatment for PDA in preterm infants.Trial RegistrationChiCTR.org ChiCTR-TRC-12002177

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“…In addition, two in vivo studies have demonstrated that ibuprofen treatment results in higher peak levels of total serum bilirubin and longer durations of phototherapy. [31], [32].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Oral Paracetamol versus Ibuprofen in Premature Infants with Patent Ductus Arteriosus: A Randomized Controlled Trial

et al. 2013

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“…[38][39][40] Ibuprofen is thought to impair biliary excretion of bilirubin and therefore it raises serum bilirubin level. 41,42 In addition, at higher serum concentration ibuprofen can displace bilirubin from its binding to albumin. 38 Indeed, a recent study showed that ibuprofen augments bilirubin toxicity in rat cortical neuronal culture.…”

Section: Introductionmentioning

confidence: 99%

Patent ductus arteriosus in the preterm infant: to treat or not to treat?

Noori

2010

J Perinatol

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Pharmacological and/or surgical closure of a hemodynamically significant patent ductus arteriosus (PDA) in the very preterm infant has been the standard of care over the past few decades. However, the rationale for closure of PDA has recently been challenged. In this article, the factors that have fueled the controversy of the approach to the management of PDA and the gap in our knowledge are reviewed in detail. In addition, the pros and cons of the different treatment strategies applied in clinical care are evaluated with a focus on discussing the available evidence in the literature.

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“…Furthermore, TB levels also tended to fall on consecutive postnatal days when TB levels would have been expected to rise as a result of the normal development of the physiologic neonatal hyperbilirubinemia (27), indicating that more bilirubin could have been shifted from plasma into the tissue space during treatment with ibuprofen. On the other hand, in two recent clinical studies, ibuprofen has been shown to slightly but significantly increase TB in infants with PDA (28,29). However, UB concentrations were not measured in these studies.…”

Section: Discussionmentioning

confidence: 59%

“…However, UB concentrations were not measured in these studies. In the study by Rheinlaender et al (28), infants treated with ibuprofen were compared with infants treated with indomethacin. Although neurodevelopmental outcome at 2 y of age did not differ between the groups, single case analysis identified four cases of adverse neurodevelopmental outcome in the ibuprofen group despite inconspicuous clinical course.…”

Section: Discussionmentioning

confidence: 99%

Displacement of Bilirubin From Albumin by Ibuprofen In Vitro

2010

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Ibuprofen binds to plasma albumin and could interfere with the binding of bilirubin in jaundiced newborn infants. Most clinical studies have not shown increased concentrations of unbound bilirubin (UB) in plasma from infants treated with ibuprofen for a patent ductus arteriosus. However, studies in vitro have not been equally conclusive. Plasma were obtained from routine samples from jaundiced newborn infants and pooled. Total and UB were measured with the peroxidase method after addition of ibuprofen or sulfisoxazole as a known bilirubin displacer. Final ibuprofen concentrations varied from 0.43 to 2.6 mM. Bilirubin concentrations were varied from 176 to 708 M by adding bilirubin to plasma samples. Ibuprofen caused a linear increase in UB up to ϩ54% at a concentration of 1.8 mM, compared with an increase of 87% by sulfisoxazole (1.32 mM). A double reciprocal plot of molar concentrations of bound versus UB at bilirubin concentrations ranging from 176 to 708 M showed a competitive displacement of bilirubin by ibuprofen. The data indicate that ibuprofen is a competitive displacer of bilirubin in vitro. Ibuprofen should be used with caution in premature infants with a significant hyperbilirubinemia. (Pediatr Res 67: 614-618, 2010) T he significance of unconjugated hyperbilirubinemia is the potential for development of bilirubin neurotoxicity and kernicterus. Most healthy term infants with a total serum bilirubin (TB) concentration reaching 425 to 680 M will, however, escape with no significant damage when treated with phototherapy and/or exchange transfusion according to guidelines (1). However, 8 to 9% of the kernicterus cases occur at a TB concentration Ͻ425 M. Kernicterus has also been reported at TB concentrations Ͻ340 M (2,3). In premature infants, bilirubin toxicity has been observed at even lower TB concentrations (4,5). More recently, high peak TB has been associated with poor long-term prognosis and adverse neurodevelopmental outcome in extremely low birth weight infants (6,7).The binding site of bilirubin on the albumin molecule is still uncertain, but most likely bilirubin binds to albumin at one high affinity binding site in a 1:1 molar ratio (3,8 -10). Clinical and experimental data have also suggested different secondary binding sites. However, these secondary binding sites may not be of any physiologic importance (10). At equilibrium, ϳ0.005% of bilirubin will be unbound bilirubin (UB). The albumin-bilirubin complex has a high molecular weight and cannot cross capillary walls, whereas UB is available for tissue distribution and elimination (9,11). Bilirubin is not toxic while bound to albumin (BB), and it is thought that the concentration of UB is a better predictor of toxicity than TB. The distribution and elimination of UB causes a shift in the equilibrium, and more bilirubin is released from albumin. The concentration of UB is influenced by several factors like the concentration of TB (2), albumin, and the binding capacity of albumin (5). Of clinical importance is the fact that the bindi...

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Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants

Abstract: In VLBW infants with PDA, ibuprofen treatment was associated with higher bilirubin levels than indomethacin.

Cited by 36 publications

References 20 publications

Comparison of Oral Paracetamol versus Ibuprofen in Premature Infants with Patent Ductus Arteriosus: A Randomized Controlled Trial

Comparison of Oral Paracetamol versus Ibuprofen in Premature Infants with Patent Ductus Arteriosus: A Randomized Controlled Trial

Patent ductus arteriosus in the preterm infant: to treat or not to treat?

Displacement of Bilirubin From Albumin by Ibuprofen In Vitro

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