Treatment of Patent Ductus Arteriosus: Indomethacin or Ibuprofen?

 

 Buy Article Permissions and Reprints

ABSTRACT

We compared ibuprofen and indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants. A retrospective comparative study was conducted at a pediatric tertiary center in preterm infants diagnosed with PDA. Infants born from January 2000 to June 2003 were treated with indomethacin, whereas infants born from July 2003 to November 2005 were treated with ibuprofen. The two treatment groups were compared. Demographic data and clinical, laboratory, and outcome data were collected from the medical files. Seventy-three infants were included in the ibuprofen group and 46 in the indomethacin group. No significant difference in efficacy was found between indomethacin and ibuprofen. Compared with ibuprofen, indomethacin treatment was associated with significantly higher mean creatinine levels and a higher percent of infants with creatinine >1.2 mg/dL, hyponatremia <120 mmol/L, and platelet level <100,000 platelets/mL³. There were no significant differences in bilirubin levels, incidence and grade of intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, rate of surgical duct ligation, sepsis, length of hospital stay, or mortality. Indomethacin and ibuprofen are equally effective for PDA closure in premature infants. Treatment with ibuprofen is safer, decreasing the risk of renal failure, thrombocytopenia, and hyponatremia.

REFERENCES

• 1 Fanos V, Benini D, Verlato G, Errico G, Cuzzolin L. Efficacy and renal tolerability of ibuprofen vs. indomethacin in preterm infants with patent ductus arteriosus.  Fundam Clin Pharmacol. 2005;  19 187-193
  CrossrefPubMedGoogle Scholar
• 2 Desfrere L, Zohar S, Morville P et al.. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method.  J Clin Pharm Ther. 2005;  30 121-132
  CrossrefPubMedGoogle Scholar
• 3 Thomas R L, Parker G C, Van Overmeire B, Aranda J V. A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus.  Eur J Pediatr. 2005;  164 135-140
  CrossrefPubMedGoogle Scholar
• 4 Su P H, Chen J Y, Su C M, Huang T C, Lee H S. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants.  Pediatr Int. 2003;  45 665-670
  CrossrefPubMedGoogle Scholar
• 5 Malviya M, Ohlsson A, Shah S. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants.  Cochrane Database Syst Rev. 2003;  (3) CD003951
  PubMedGoogle Scholar
• 6 Fujii A M, Brown E, Mirochnick M, O'Brien S, Kaufman G. Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus.  J Perinatol. 2002;  22 535-540
  Google Scholar
• 7 Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants.  Cochrane Database Syst Rev. 2008;  (1) CD003481
  PubMedGoogle Scholar
• 8 Gimeno Navarro A, Modesto Alapont V, Morcillo Sopena F, Fernández Gilino C, Izquierdo Macián I, Gutiérrez Laso A. [Ibuprofen versus indomethacin in the preterm persistent patent ductus arteriosus therapy: review and meta-analysis].  An Pediatr (Barc). 2007;  67 309-318
  PubMedGoogle Scholar
• 9 Sekar K C, Corff K E. Treatment of patent ductus arteriosus: indomethacin or ibuprofen?.  J Perinatol. 2008;  28(Suppl 1) S60-S62
  CrossrefPubMedGoogle Scholar
• 10 Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli F F. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus.  J Pediatr. 1999;  135 733-738
  CrossrefPubMedGoogle Scholar
• 11 Lin Y J, Tsai Y J, Chen J S et al.. Renal effects and urinary excretion of prostaglandin following indomethacin therapy in premature infants with patent ductus arteriosus.  Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1995;  36 104-107
  PubMedGoogle Scholar
• 12 Grosfeld J L, Chaet M, Molinari F et al.. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin.  Ann Surg. 1996;  224 350-355 discussion 355-357
  CrossrefPubMedGoogle Scholar
• 13 Van Overmeire B, Van de Broek H, Van Laer P, Weyler J, Vanhaesebrouck P. Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome.  J Pediatr. 2001;  138 205-211
  CrossrefPubMedGoogle Scholar
• 14 Christmann V, Liem K D, Semmekrot B A, van de Bor M. Changes in cerebral, renal and mesenteric blood flow velocity during continuous and bolus infusion of indomethacin.  Acta Paediatr. 2002;  91 440-446
  CrossrefPubMedGoogle Scholar
• 15 Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus.  J Pediatr. 1997;  131 549-554
  PubMedGoogle Scholar
• 16 Hammerman C, Kaplan M. Comparative tolerability of pharmacological treatments for patent ductus arteriosus.  Drug Saf. 2001;  24 537-551
  CrossrefPubMedGoogle Scholar
• 17 Van Overmeire B, Smets K, Lecoutere D et al.. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus.  N Engl J Med. 2000;  343 674-681
  CrossrefPubMedGoogle Scholar
• 18 Adamska E, Helwich E, Rutkowska M, Zacharska E, Piotrowska A. [Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants].  Med Wieku Rozwoj. 2005;  9(3 Pt 1) 335-354
  PubMedGoogle Scholar
• 19 Su B H, Lin H C, Chiu H Y, Hsieh H Y, Chen H H, Tsai Y C. Comparison of ibuprofen and indomethacin for early-targeted treatment of patent ductus arteriosus in extremely premature infants: a randomised controlled trial.  Arch Dis Child Fetal Neonatal Ed. 2008;  93 F94-F99
  PubMedGoogle Scholar
• 20 Aranda J V, Thomas R. Systematic review: intravenous ibuprofen in preterm newborns.  Semin Perinatol. 2006;  30 114-120
  CrossrefPubMedGoogle Scholar
• 21 Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants.  Cochrane Database Syst Rev. 2005;  (4) CD003481
  PubMedGoogle Scholar
• 22 Pai V B, Sakadjian A, Puthoff T D. Ibuprofen lysine for the prevention and treatment of patent ductus arteriosus.  Pharmacotherapy. 2008;  28 1162-1182
  CrossrefPubMedGoogle Scholar
• 23 Betkerur M V, Yeh T F, Miller K, Glasser R J, Pildes R S. Indomethacin and its effect on renal function and urinary kallikrein excretion in premature infants with patent ductus arteriosus.  Pediatrics. 1981;  68 99-102
  PubMedGoogle Scholar
• 24 Van Overmeire B, Vanhagendoren S, Schepens P J et al.. The influence of ibuprofen-lysine on unbound bilirubin plasma levels in preterm neonates.  Pediatr Res. 2004;  55 474A
  PubMedGoogle Scholar
• 25 Hasan J, Beharry K D, Gharraee Z et al.. Early postnatal ibuprofen and indomethacin effects in suckling and weanling rat kidneys.  Prostaglandins Other Lipid Mediat. 2008;  85 81-88
  CrossrefPubMedGoogle Scholar
• 26 Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants.  Am J Perinatol. 2007;  24 339-345
  Article in Thieme ConnectPubMedGoogle Scholar
• 27 Van Overmeire B. The use of ibuprofen in neonates in the treatment of patent ductus arteriosus.  Int J Clin Pract Suppl. 2003;  (135) 23-27
  PubMedGoogle Scholar
• 28 Chotigeat U, Jirapapa K, Layangkool T. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants.  J Med Assoc Thai. 2003;  86(Suppl 3) S563-S569
  PubMedGoogle Scholar
• 29 Heyman E, Morag I, Batash D, Keidar R, Baram S, Berkovitch M. Closure of patent ductus arteriosus with oral ibuprofen suspension in premature newborns: a pilot study.  Pediatrics. 2003;  112 e354
  CrossrefPubMedGoogle Scholar
• 30 Van Overmeire B, Follens I, Hartmann S, Creten W L, Van Acker K J. Treatment of patent ductus arteriosus with ibuprofen.  Arch Dis Child Fetal Neonatal Ed. 1997;  76 F179-F184
  CrossrefPubMedGoogle Scholar
• 31 Plavka R, Svihovec P, Borek I et al.. Ibuprofen vs indomethacin in the treatment of patent ductus arteriosus in very premature neonates.  Pediatr Res. 2001;  49 375A
  PubMedGoogle Scholar
• 32 Ibuprofen for closure of patent ductus arteriosus.  Arch Dis Child. 2001;  84 81
  CrossrefPubMedGoogle Scholar
• 33 Yeh T F, Achanti B, Patel H, Pildes R S. Indomethacin therapy in premature infants with patent ductus arteriosus—determination of therapeutic plasma levels.  Dev Pharmacol Ther. 1989;  12 169-178
  PubMedGoogle Scholar
• 34 Yeh T F, Luken J A, Thalji A, Raval D, Carr I, Pildes R S. Intravenous indomethacin therapy in premature infants with persistent ductus arteriosus—a double-blind controlled study.  J Pediatr. 1981;  98 137-145
  PubMedGoogle Scholar
• 35 Petersen S, Christensen N C, Møller Jensen K, Ryssing E. Serum indomethacin concentrations after intravenous administration to preterm infants with patent ductus arteriosus.  Acta Paediatr Scand. 1981;  70 729-733
  CrossrefPubMedGoogle Scholar
• 36 Hammerman C, Zaia W, Wu H H. Severe hyponatremia with indomethacin—a more serious toxicity than previously realized?.  Dev Pharmacol Ther. 1985;  8 260-267
  PubMedGoogle Scholar
• 37 Keady S, Grosso A. Ibuprofen in the management of neonatal patent ductus arteriosus.  Intensive Crit Care Nurs. 2005;  21 56-58
  CrossrefPubMedGoogle Scholar
• 38 Rault R M. Case report: hyponatremia associated with nonsteroidal antiinflammatory drugs.  Am J Med Sci. 1993;  305 318-320
  CrossrefPubMedGoogle Scholar
• 39 Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards A D. Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus.  Pediatr Res. 2000;  47 36-42
  CrossrefPubMedGoogle Scholar
• 40 Kumar R K, Yu V Y. Prolonged low-dose indomethacin therapy for patent ductus arteriosus in very low birthweight infants.  J Paediatr Child Health. 1997;  33 38-41
  CrossrefPubMedGoogle Scholar
• 41 Sheffield M J, Schmutz N, Lambert D K, Henry E, Christensen R D. Ibuprofen lysine administration to neonates with a patent ductus arteriosus: effect on platelet plug formation assessed by in vivo and in vitro measurements.  J Perinatol. 2009;  29 39-43
  CrossrefPubMedGoogle Scholar
• 42 Aly H, Lotfy W, Badrawi N, Ghawas M, Abdel-Meguid I E, Hammad T A. Oral Ibuprofen and ductus arteriosus in premature infants: a randomized pilot study.  Am J Perinatol. 2007;  24 267-270
  Article in Thieme ConnectPubMedGoogle Scholar
• 43 Van Overmeire B, Allegaert K, Casaer A et al.. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial.  Lancet. 2004;  364 1945-1949
  CrossrefPubMedGoogle Scholar
• 44 Lago P, Bettiol T, Salvadori S et al.. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial.  Eur J Pediatr. 2002;  161 202-207
  CrossrefPubMedGoogle Scholar
• 45 De Carolis M P, Romagnoli C, Polimeni V et al.. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants.  Eur J Pediatr. 2000;  159 364-368
  CrossrefPubMedGoogle Scholar
• 46 Hammerman C, Shchors I, Jacobson S et al.. Ibuprofen versus continuous indomethacin in premature neonates with patent ductus arteriosus: is the difference in the mode of administration?.  Pediatr Res. 2008;  64 291-297
  CrossrefPubMedGoogle Scholar
• 47 Gournay V, Roze J C, Kuster A et al.. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial.  Lancet. 2004;  364 1939-1944
  CrossrefPubMedGoogle Scholar
• 48 Fowlie P W, Davis P G. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.  Cochrane Database Syst Rev. 2002;  (3) CD000174
  PubMedGoogle Scholar
• 49 Shah S S, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.  Cochrane Database Syst Rev. 2006;  (1) CD004213
  PubMedGoogle Scholar
• 50 Gournay V, Savagner C, Thiriez G, Kuster A, Rozé J C. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants.  Lancet. 2002;  359 1486-1488
  CrossrefPubMedGoogle Scholar
• 51 Zecca E, Romagnoli C, De Carolis M P, Costa S, Marra R, De Luca D. Does Ibuprofen increase neonatal hyperbilirubinemia?.  Pediatrics. 2009;  124 480-484
  CrossrefPubMedGoogle Scholar
• 52 Hansen T W. Ibuprofen for closure of patent ductus arteriosus: is it really safe in hyperbilirubinaemic infants?.  Eur J Pediatr. 2003;  162 356 author reply 357
  PubMedGoogle Scholar
• 53 Cooper-Peel C, Brodersen R, Robertson A. Does ibuprofen affect bilirubin-albumin binding in newborn infant serum?.  Pharmacol Toxicol. 1996;  79 297-299
  CrossrefPubMedGoogle Scholar
• 54 Ahlfors C E. Effect of ibuprofen on bilirubin-albumin binding.  J Pediatr. 2004;  144 386-388
  PubMedGoogle Scholar
• 55 Rheinlaender C, Helfenstein D, Walch E, Berns M, Obladen M, Koehne P. Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants.  Acta Paediatr. 2009;  98 36-42
  CrossrefPubMedGoogle Scholar
• 56 Lam B C, Wong H N, Yeung C Y. Effect of indomethacin on binding of bilirubin to albumin.  Arch Dis Child. 1990;  65(7 Spec No) 690-691
  CrossrefPubMedGoogle Scholar
• 57 Shankaran S, Pantoja A, Poland R L. Indomethacin and bilirubin-albumin binding.  Dev Pharmacol Ther. 1982;  4 124-131
  PubMedGoogle Scholar

Prof. N. LinderM.D. 

Department of Neonatology, Rabin Medical Center

2 Denmark St. Petach Tikva 49100, Israel

Email: linderm@netvision.net.il