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Pediatric Drugs

, Volume 21, Issue 2, pp 113–121 | Cite as

Efficacy and Safety of Oral Paracetamol vs. Oral Ibuprofen in the Treatment of Symptomatic Patent Ductus Arteriosus in Premature Infants

  • Birol KarabulutEmail author
  • Sebnem Paytoncu
Original Research Article
  • 46 Downloads

Abstract

Background

The ductus arteriosus (DA) is situated between the aortic arch and the pulmonary artery in fetal circulation, and its closure is one of the most important changes required for the transition to extrauterine life. Prolonged duration of patent DA (PDA) impairs hemodynamics and contributes both to morbidity associated with prematurity and to mortality. Therefore, when best to initiate treatment and what drug to use as first-line treatment to close the ductus is important.

Objective

The aim of this study was to compare the efficacy and side effects of the oral forms of ibuprofen and paracetamol and to contribute to the literature investigating the first drug to be selected in the medical treatment of PDA.

Methods

This observational, retrospective cohort study was conducted in infants born at ≤ 28 weeks’ gestation and admitted to our Neonatal Intensive Care Unit (Manisa Merkezefendi State Hospital, Manisa, Turkey) between February 2015 and April 2018. Included infants were born at ≤ 28 weeks’ gestation, had PDA-related clinical findings and hemodynamically significant PDA on echocardiography, and received oral ibuprofen or oral paracetamol therapy as the closure treatment.

Results

The most common clinical findings for the diagnosis of PDA were hyperdynamic circulation, tachycardia, and increased oxygen requirement. In total, 43 of the 51 (84.3%) premature infants in the ibuprofen group and 32 of the 36 (88.8%) in the paracetamol group achieved PDA closure after the first treatment cycle. There was no statistically significant difference between the two groups in terms of respiratory morbidity, renal and liver function, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity, length of hospital stay, and mortality.

Conclusions

Our results indicate that oral paracetamol was as effective as oral ibuprofen in the medical treatment of PDA. In addition, both drugs were considered well-tolerated in terms of effects on kidney, liver, and intestinal functions. Our results demonstrate that oral paracetamol can be used effectively and safely as the first-line treatment of PDA.

Notes

Acknowledgements

The authors acknowledge Manisa Merkezefendi State Hospital for help with data collection.

Compliance with Ethical Standards

Conflict of interest

B. Karabulut, S. Paytoncu have no conflicts of interest that are directly relevant to the content of this article.

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

References

  1. 1.
    Clyman RI. Mechanisms regulating the ductus arteriosus. Biol Neonate. 2006;89(4):330–5.CrossRefGoogle Scholar
  2. 2.
    Weinberg JG, Evans FJ, Burns KM, Pearson GD, Kaltman JR. Surgical ligation of patent ductus arteriosus in premature infants: trends and practice variation. Cardiol Young. 2015;23:1–8.Google Scholar
  3. 3.
    Mirea L, Sankaran K, Seshia M, et al. Treatment of patent ductus arteriosus and neonatal mortality/morbidities: adjustment for treatment selection bias. J Pediatr. 2012;161(4):689–694e1.CrossRefGoogle Scholar
  4. 4.
    Sehgal A, McNamara PJ. The ductus arteriosus: a refined approach. Semin Perinatol. 2012;36(2):105–13.CrossRefGoogle Scholar
  5. 5.
    Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol. 2010;30(4):241–52.  https://doi.org/10.1038/jp.2010.3.CrossRefGoogle Scholar
  6. 6.
    Demirel G, Erdeve O, Dilmen U. Pharmacological management of PDA: oral versus intravenous medications. Curr Clin Pharmacol. 2012;7(4):263–70.CrossRefGoogle Scholar
  7. 7.
    Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2012;97(4):F279–83.  https://doi.org/10.1136/archdischild-2011-300532.CrossRefGoogle Scholar
  8. 8.
    Erdeve O, Gokmen T, Altug N, Dilmen U. Oral versus intravenous ibuprofen: which is better in closure of patent ductus arteriosus? Pediatrics. 2009;123:763.CrossRefGoogle Scholar
  9. 9.
    Erdeve O, Sarici SU, Sari E, Gok F. Oral ibuprofen-induced acute renal failure in a preterm infant. Pediatr Nephrol. 2008;23:1565–7.CrossRefGoogle Scholar
  10. 10.
    Yurttutan S, Oncel MY, Arayici S, Uras N, Altug N, Erdeve O, 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.CrossRefGoogle Scholar
  11. 11.
    Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev. 2015;(3):CD010061.  https://doi.org/10.1002/14651858.cd010061.pub3.
  12. 12.
    Köksal N, Aygün C, Uras N. Turkish Neonatal Society guideline on the management of patent ductus arteriosus in preterm infants. Turk Pediatri Ars. 2018;53(Suppl 1):S76–87.Google Scholar
  13. 13.
    Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin N Am. 1986;33:179–201.CrossRefGoogle Scholar
  14. 14.
    Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92:529–34.CrossRefGoogle Scholar
  15. 15.
    International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005;123:991–9.CrossRefGoogle Scholar
  16. 16.
    Hung YC, Yeh JL, Hsu JH. Molecular mechanisms for regulating postnatal ductus arteriosus closure. Int J Mol Sci. 1861;2018:19.  https://doi.org/10.3390/ijms19071861.Google Scholar
  17. 17.
    Clyman RI. Patent ductus arteriosus in the preterm infant. In: Gleason CA, Devaskar S, editors. Avery’s diseases of the newborn. 9th ed. Philadelphia: Saunders; 2012. p. 751–61.CrossRefGoogle Scholar
  18. 18.
    Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics. 2010;125:1020–30.CrossRefGoogle Scholar
  19. 19.
    Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Engl J Med. 1976;295:530–3.CrossRefGoogle Scholar
  20. 20.
    Friedman WF, Hirschklau MJ, Printz MP, Pitlick PT, Kirkpatrick SE. Pharmacologic closure of patent ductus arteriosus in the premature infant. N Engl J Med. 1976;295:526–9.CrossRefGoogle Scholar
  21. 21.
    Grèen K, Drvota V, Vesterqvist O. Pronounced reduction of in vivo prostacyclin synthesis in humans by acetaminophen (paracetamol). Prostaglandins. 1989;37:311–5.CrossRefGoogle Scholar
  22. 22.
    Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA. 2002;99:13926–31.CrossRefGoogle Scholar
  23. 23.
    Lucas R, Warner TD, Vojnovic I, Mitchell JA. Cellular mechanisms of acetaminophen: role of cyclooxygenase. FASEB J. 2005;19:635–7.CrossRefGoogle Scholar
  24. 24.
    Kulmacz RJ, Wang LH. Comparison of hydroperoxide initiator requirements for the cyclooxygenase activities of prostaglandin H synthase-1 and -2. J Biol Chem. 1995;270:24019–23.CrossRefGoogle Scholar
  25. 25.
    Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology. 2013;21:201–32.CrossRefGoogle Scholar
  26. 26.
    Antonucci R, Cuzzolin L, Arceri A, Dessì A, Fanos V. Changes in urinary PGE2 after ibuprofen treatment in preterm infants with patent ductus arteriosus. Eur J Clin Pharmacol. 2009;65:223–30.CrossRefGoogle Scholar
  27. 27.
    Yang B, Gao X, Ren Y, Wang Y, Zhang Q. Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: A randomized controlled trial. Exp Ther Med. 2016;12:2531–6.CrossRefGoogle Scholar
  28. 28.
    Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database Syst Rev. 2015;3:CD010061.Google Scholar
  29. 29.
    Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PloS One. 2013;8:e77888.CrossRefGoogle Scholar
  30. 30.
    Fanos V, Antonucci R, Zaffanello M. Ibuprofen and acute kidney injury in the newborn. Turk J Pediatr. 2010;52:231–8.Google Scholar
  31. 31.
    Tiker F, Yildirim SV. Acute renal impairment after oral ibuprofen for medical closure of patent ductus arteriosus. Indian Pediatr. 2007;44:54–5.Google Scholar
  32. 32.
    Erdeve O, Sarici SU, Sari E, Gok F. Oral-ibuprofen-induced acute renal failure in a preterm infant. Pediatr Nephrol Berl Ger. 2008;23:1565–7.CrossRefGoogle Scholar
  33. 33.
    Su PH, Chen JY, Su CM, et al. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Pediatr Int. 2003;45(6):665–70.CrossRefGoogle Scholar
  34. 34.
    Vieux R, Desandes R, Boubred F, et al. Ibuprofen in very preterm infants impairs renal function for the first month of life. Pediatr Nephrol. 2010;25(2):267–74.CrossRefGoogle Scholar
  35. 35.
    El-Mashad AE, El-Mahdy H, El Amrousy D, et al. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr. 2017;176:233–40.CrossRefGoogle Scholar
  36. 36.
    Zecca E, Romagnoli C, De Carolis MP, Costa S, Marra R, De Luca D. Does ibuprofen increase neonatal hyperbilirubinemia? Pediatrics. 2009;124(2):480–4.  https://doi.org/10.1542/peds.2008-2433.CrossRefGoogle Scholar
  37. 37.
    Rheinlaender C, Helfenstein D, Walch E, et al. Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants. Acta Paediatr. 2009;98(1):36–42.CrossRefGoogle Scholar
  38. 38.
    Ahlfors CE. Effect of ibuprofen on bilirubin–albumin binding. J Pediatr. 2004;144:386–8.CrossRefGoogle Scholar
  39. 39.
    Cooper-Peel C, Brodersen R, Robertson A. Does ibuprofen affect bilirubin–albumin binding in newborn infant serum. Pharmacol Toxicol. 1996;79:297–9.CrossRefGoogle Scholar
  40. 40.
    Soligard HT, Nilsen OG, Bratlid D. Displacement of bilirubin from albumin by ibuprofen in vitro. Pediatr Res. 2010;67:614–8.CrossRefGoogle Scholar
  41. 41.
    Diot C, Kibleur Y, Desfrere L. Effect of ibuprofen on bilirubin–albumin binding in vitro at concentrations observed during treatment of patent ductus arteriosus. Early Hum Dev. 2010;86:315–7.CrossRefGoogle Scholar
  42. 42.
    Wu M, Wan J. COX-3: is it the target of acetaminophen? Prog Physiol Sci. 2010;41:40–2.Google Scholar
  43. 43.
    Walker KS, Matheson PJ, Galganski LA, Garrison RN, Downard CD. Application of prostaglandin E2 improves ileal blood flow in NEC. J Pediatr Surg. 2014;49:945–9 (discussion 949).CrossRefGoogle Scholar
  44. 44.
    Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics. 2011;128(6):e1618–21.CrossRefGoogle Scholar
  45. 45.
    Le J, Gales MA, Gales BJ. Acetaminophen for patent ductus arteriosus. Ann Pharmacother. 2015;49:241–6.CrossRefGoogle Scholar
  46. 46.
    Allegaert K, Anderson B, Simons S, van Overmeire B. Paracetamol to induce ductus arteriosus closure: is it valid? Arch Dis Child. 2013;98:462–6.CrossRefGoogle Scholar
  47. 47.
    Oncel MY, Yurttutan S, Uras N, Altug N, Ozdemir R, Ekmen S, Erdeve O, Dilmen U. 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.CrossRefGoogle Scholar
  48. 48.
    Nadir E, Kassem E, Foldi S, Hochberg A, Feldman M. Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol. 2014;34:748–9.CrossRefGoogle Scholar
  49. 49.
    Sinha R, Negi V, Dalal SS. An interesting observation of PDA closure with oral paracetamol in preterm neonates. J Clin Neonatol. 2013;2:30–2.CrossRefGoogle Scholar
  50. 50.
    Ozdemir OM, Doğan M, Küçüktaşçı K, Ergin H, Sahin O. Paracetamol therapy for patent ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol. 2014;35:276–9.CrossRefGoogle Scholar
  51. 51.
    Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolat FE, Dilmen U. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr. 2014;164:510–514.e.1.CrossRefGoogle Scholar
  52. 52.
    Bagheri MM, Niknafs P, Sabsevari F, Torabi MH, Bijari BB, Noroozi E, Mossavi H. Comparison of oral acetaminophen versus ibuprofen in premature infants with patent ductus arteriosus. Iran J Pediatr. 2016;26(4):e3975.CrossRefGoogle Scholar
  53. 53.
    Balachander B, Mondal N, Bhat V, Adhisivam B, Kumar M, Satheesh S, Thulasingam M. Comparison of efficacy of oral paracetamol versus ibuprofen for PDA closure in preterms—a prospective randomized clinical trial. J Matern Fetal Neonatal Med. 2018.  https://doi.org/10.1080/14767058.2018.1525354.Google Scholar
  54. 54.
    El-Farrash RA, El Shimy MS, El-Sakka AS, Ahmed MG, Abdel-Moez DG. Efficacy and safety of oral paracetamol versus oral ibuprofen for closure of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Matern Fetal Neonatal Med. 2018.  https://doi.org/10.1080/14767058.2018.1470235.Google Scholar
  55. 55.
    Al-Lawama M, Alammori I, Abdelghani T, Badran E. Oral paracetamol versus oral ibuprofen for treatment of patent ductus arteriosus. J Int Med Res. 2017;46(2):811–818.CrossRefGoogle Scholar
  56. 56.
    Tekgunduz KS, Ceviz N, Demirelli Y, Olgun H, Caner I, Sahin IO, et al. Intravenous paracetamol for patent ductus arteriosus in premature infants—a lower dose is also effective. Neonatology. 2013;104:6–7.CrossRefGoogle Scholar
  57. 57.
    Alan S, Kahvecioglu D, Erdeve O, Atasay B, Arsan S. Is paracetamol a useful treatment for ibuprofen-resistant patent ductus arteriosus? Neonatology. 2013;104:168–9.CrossRefGoogle Scholar
  58. 58.
    Sharma J, Barr SM, Geng Y, Yun Y, Higgins RD. Ibuprofen improves oxygen-induced retinopathy in a mouse model. Curr Eye Res. 2003;27:309–14.CrossRefGoogle Scholar
  59. 59.
    Viberg H, Eriksson P, Gordh T, Fredriksson A. Paracetamol (acetaminophen) administration during neonatal brain development affects cognitive function and alters its analgesic and anxiolytic response in adult male mice. Toxicol Sci. 2014;138(1):139–47.CrossRefGoogle Scholar
  60. 60.
    Bauer AZ, Kriebel D. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health. 2013;9(12):41.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Pediatrics, Division of NeonatologyIzmir Katip Celebi University Ataturk Training and Research HospitalIzmirTurkey
  2. 2.Pediatrics, Division of Pediatric CardiologyManisa Merkezefendi State HospitalManisaTurkey

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