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European Journal of Pediatrics

, Volume 176, Issue 2, pp 233–240 | Cite as

Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates

  • Abd El-Rahman El-Mashad
  • Heba El-Mahdy
  • Doaa El AmrousyEmail author
  • Marwa Elgendy
Original Article

Abstract

In this prospective study, we compared the efficacy and side effects of indomethacin, ibuprofen, and paracetamol in patent ductus arteriosus (PDA) closure in preterm neonates. Three hundred preterm neonates with hemodynamically significant PDA (hs-PDA) admitted at our neonatal intensive care unit were enrolled in the study. They were randomized into three groups. Group I (paracetamol group) received 15 mg/kg/6 h IV paracetamol infusion for 3 days. Group II (ibuprofen group) received 10 mg/kg IV ibuprofen infusion followed by 5 mg/kg/day for 2 days. Group III (indomethacin group) received 0.2 mg/kg/12 h indomethacin IV infusion for three doses. Laboratory investigations such as renal function test, liver function test, complete blood count, and blood gases were conducted in addition to echocardiographic examinations. All investigations were done before and 3 days after treatment. There was no significant difference between all groups regarding efficacy of PDA closure (P = 0.868). There was a significant increase in serum creatinine levels and serum blood urea nitrogen (BUN) in the ibuprofen and indomethacin groups (P < 0.001). There was a significant reduction in platelet count and urine output (UOP) in both ibuprofen and indomethacin groups (P < 0.001). There was a significant increase in bilirubin levels in only the ibuprofen group (P = 0.003). No significant difference of hemoglobin (HB) level or liver enzymes in all groups (P > 0.05). Ventilatory settings improved significantly in patients with successful closure of PDA than those with failed PDA closure (P < 0.001).

Conclusion: Paracetamol is as effective as indomethacin and ibuprofen in closure of PDA in preterm neonates and has less side effects mainly on renal function, platelet count, and GIT bleeding.

What is Known:

Hemodynamically significant patent ductus arteriosus has many complications for preterm and low birth weight neonates and better to be closed. Many drugs were used for medical closure of PDA e.g. indomethacin, ibuprofen and recently paracetamol. Many studies compare safety and efficacy of paracetamol with either indomethacin or ibuprofen.

What is New:

It is the first large study that compares the efficacy and side effects of the three drugs in one study.

Keywords

PDA closure Preterm neonate Paracetamol Ibuprofen Indomethacin 

Abbreviations

BUN

Blood urea nitrogen

COX

Cyclooxygenase

GIT

Gastrointestinal tract

HB

Hemoglobin

Hs-PDA

Hemodynamically significant patent ductus arteriosus

IV

Intravenous

IVH

Intraventricular hemorrhage

MV

Mechanical ventilation

NEC

Necrotizing enterocolitis

NICU

Neonatal intensive care unit

NSAID

Nonsteroidal anti-inflammatory drugs

PDA

Patent ductus arteriosus

PG

Prostaglandin

PIP

Positive intermittent pressure

ROP

Retinopathy of prematurity

SGOT

Serum glutamate-oxaloacetic transaminase

SGPT

Serum glutamate-pyruvate transaminase

UOP

Urinary output

Notes

Authors’ contributions

Abd El-Rahman El-Mashad: the idea of the research, supervising the work of research, and revising and approving the manuscript.

Heba El-Mahdy: selecting patients and dividing them into groups, supervising and following up patients, and revising the manuscript.

Doaa El-Amrousy: performing the echocardiography, writing the manuscript, doing the statistical analysis, and following up the patients.

Marwa Elgendy: following up the patients, gathering the data, and helping in writing the manuscript.

Compliance with ethical standards

Funding

None to declare.

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants

The study was approved by the local Ethics Committee of Faculty of Medicine of our University and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all parents of the participants included in the study.

References

  1. 1.
    Alagarsamy S, Chhabra M, Gudavalli M, Nadroo AM, Sutija VG, Yugrakh D (2005) Comparison of clinical criteria with echocardiographic findings in diagnosing PDA in preterm infants. J Perinat Med 33:161–164CrossRefPubMedGoogle Scholar
  2. 2.
    Alan S, Kahyecioglu D, Erdeve O, Atasay B, Arsan S (2013) Is paracetamol a useful treatment for ibuprofen resistant patent ductus arteriosus? Neonatology 104:168–169CrossRefPubMedGoogle Scholar
  3. 3.
    Allegaert K, Anderson BJ, Naulaers G, de Hoon J, Verbesselt R, Debeer A, Devliegar H, Tibboel D (2004) Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm babies. Eur J Clin Pharmacol 60:191–197CrossRefPubMedGoogle Scholar
  4. 4.
    Anderson BJ, Allegaert K (2009) Intravenous neonatal paracetamol dosing: the magic of 10 days. Paediatr Anaesth 19(4):289–295CrossRefPubMedGoogle Scholar
  5. 5.
    Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H (2013) Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One 8:e778–e788Google Scholar
  6. 6.
    Dani C (2014) Ibuprofen and paracetamol for patent ductus arteriosus. J Pediatr Neonat Individual Med 3(2):1–4Google Scholar
  7. 7.
    Dash SK, Kabra NS, Avashthi BS, Sharma SR, Padhi P, Ahmed J (2015) Enteral paracetamol or intravenous indomethacin for closure of patent ductus arteriosus in preterm neonates: a randomized controlled study. Indian Pediatr 52:573–578CrossRefPubMedGoogle Scholar
  8. 8.
    Hammerman C, Bin-nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D (2001) Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics 128(6):1618–1621CrossRefGoogle Scholar
  9. 9.
    Jacqz-Aigrain E, Anderson BJ (2006) Pain control: nonsteroidal anti-inflammatory agents. Semin Fetal Neonatal Med 11(4):251–259CrossRefPubMedGoogle Scholar
  10. 10.
    Jan SL, Hwang B, YC F, Chi CS (2004) Prediction of ductus arteriosus closure by neonatal screening echocardiography. Int J Cardiovasc Imaging 20:349–356CrossRefPubMedGoogle Scholar
  11. 11.
    Jim WT, Chiu NC, Chen MR, Hung HY, Kao HA, Hsu CH, Chang JH (2005) Cerebral hemodynamic change and intraventricular hemorrhage in very low birth weight infants with patent ductus arteriosus. Ultrasound Med Biol 31:197–202CrossRefPubMedGoogle Scholar
  12. 12.
    Jones LJ, Craven PD, Attia J, Thakkinstian A, Wright I (2010) Network meta-analyses of indomethacin versus ibuprofen versus placebo for PDA in preterm infants. Arch Dis Child Fetal Neonatal 164(3):135–140Google Scholar
  13. 13.
    Lee LCL, Tillett A, Tulloh R, Yates R, Kelsall W (2006) Outcome following patent ductus arteriosus ligation in premature infants: a retrospective cohort analysis. BMC Pediatr 6:15–21CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lee CH, Chen HN, Tsao L (2012) Oral ibuprofen versus intravenous indomethacin for closure of patent ductus arteriosus in very low birth weight infants. Pediatr Neonatol 53(6):346–353CrossRefPubMedGoogle Scholar
  15. 15.
    Lin CC, Hsieh KS, Huang TC, Weng KP (2009) Closure of large patent ductus arteriosus in infants. Am J Cardiol 103(6):857–861CrossRefPubMedGoogle Scholar
  16. 16.
    Lucas R, Warner TD, Vojnovic I, Mitchell JA (2005) Cellular mechanisms of acetaminophen: role of cyclo-oxygenase. FASEB J 19(6):635–637PubMedGoogle Scholar
  17. 17.
    Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT (2000) Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 67(3):275–282CrossRefPubMedGoogle Scholar
  18. 18.
    McNamara PJ, Sehgal A (2007) Towards rational management of the patent ductus arteriosus: the need for disease staging. Arch Dis Child Fetal Neonatal Ed 92(6):F424–F427CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Meibner U, Charrabatry R, Topf HG, Rascher W, Schroth M (2012) Improved closure of patent ductus arteriosus with high doses of ibuprofen. Pediatr Cardiol 33:586–590CrossRefGoogle Scholar
  20. 20.
    Moll M, Goelz R, Naegele T, Poets CF (2011) Are recommended phototherapy thresholds safe enough for extremely low birth weight (ELBW) infants? A report on 2 ELBW infants with kernicterus despite only moderate hyperbilirubinemia. Neonatology 99(2):90–94CrossRefPubMedGoogle Scholar
  21. 21.
    Oncel MY, Yurttutan S, Degirmencioglu H, Uras N, Altug N, Erdeve O, Dilmen U (2013) Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology 103(3):166–169CrossRefPubMedGoogle Scholar
  22. 22.
    Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolate FE, Dilmen U (2014) Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 164:510–514CrossRefPubMedGoogle Scholar
  23. 23.
    Peng S, Duggan A (2005) Gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs. Expert Opin Drug Safe 4(2):157–169CrossRefGoogle Scholar
  24. 24.
    Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF (1999) Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. J Pediatr 135:733–738CrossRefPubMedGoogle Scholar
  25. 25.
    Rheinlaender C, Helfenstein D, Walch E, Berns M, Obladen M, Koehne P (2009) Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants. Acta Paediatr 98(1):36–42CrossRefPubMedGoogle Scholar
  26. 26.
    Roofthooft DW, van Beynum IM, de Klerk JC, van Dijk M, van den Anker JN, Reiss IK, Tibboel D, Simons SH (2015) Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure. Eur J Pediatr 174(11):1433–1440CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Schmidt B, Roberts RS, Fanaroff A (2006) Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the trial of indomethacin prophylaxis in preterms (TIPP). J Pediatr 148:730–734CrossRefPubMedGoogle Scholar
  28. 28.
    Starling M, Elliott R (1974) The effects of prostaglandins, prostaglandin inhibitors, and oxygen on the closure of the ductus arteriosus, pulmonary arteries and umbilical vessels invitro. Prostaglandins 8:187–203CrossRefPubMedGoogle Scholar
  29. 29.
    Stefano JL, Abbasi S, Pearlman SA, Spear ML, Esterly KL, Bhutani VK (1991) Closure of the ductus arteriosus with indomethacin in ventilated neonates with respiratory distress syndrome. Effects of pulmonary compliance and ventilation. Am Rev Respir Dis 143:236–239CrossRefPubMedGoogle Scholar
  30. 30.
    Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, Groote KD, Langhendries JP (2000) A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 343:674–681CrossRefPubMedGoogle Scholar
  31. 31.
    Vane JR, Botting RM (1997) Mechanism of action of anti-inflammatory drugs. In: Sinzinger H, Samuelsson B, Vane JR, Paoletti R, Ramwell P, Wong PY-K (eds) Recent advances in prostaglandin, thromboxane, and leukotriene research. Advances in experimental medicine and biology. Plenum Press, New York, pp. 131–138CrossRefGoogle Scholar
  32. 32.
    Yang C, Lee J (2008) Factors affecting successful closure of hemodynamically significant patent ductus arteriosus with indomethacin in extremely low birth weight infants. World J Pediatr 4(2):91–96CrossRefPubMedGoogle Scholar
  33. 33.
    Yurttutan S, Oncel MY, Arayici S, Uras N, Altug N, Erdeve O, Dilmen U (2013) A different first-choice drug in the medical management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med 26(8):825–827CrossRefPubMedGoogle Scholar
  34. 34.
    Zecca E, Romagnoli C, De Carolis M, Costa S, Marra R, De Luca D (2009) Does ibuprofen increase neonatal hyperbilirubinemia? Pediatrics 124(2):480–484CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Abd El-Rahman El-Mashad
    • 1
  • Heba El-Mahdy
    • 1
  • Doaa El Amrousy
    • 1
    Email author
  • Marwa Elgendy
    • 1
  1. 1.Pediatric DepartmentTanta University HospitalTantaEgypt

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