The effects of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants

미숙아 동맥관 개존 치료에서 indomethacin과 ibuprofen의 효과

  • Choi, Wooksun (Department of Pediatrics, Korea University College of Medicine) ;
  • Shin, Jung-Yeon (Department of Pediatrics, Korea University College of Medicine) ;
  • Choi, Byung Min (Department of Pediatrics, Korea University College of Medicine) ;
  • Eun, Baik-Lin (Department of Pediatrics, Korea University College of Medicine) ;
  • Yoo, Kee Hwan (Department of Pediatrics, Korea University College of Medicine) ;
  • Hong, Young Sook (Department of Pediatrics, Korea University College of Medicine) ;
  • Lee, Joo Won (Department of Pediatrics, Korea University College of Medicine)
  • 최욱선 (고려대학교 의과대학 소아과학교실) ;
  • 신정연 (고려대학교 의과대학 소아과학교실) ;
  • 최병민 (고려대학교 의과대학 소아과학교실) ;
  • 은백린 (고려대학교 의과대학 소아과학교실) ;
  • 유기환 (고려대학교 의과대학 소아과학교실) ;
  • 홍영숙 (고려대학교 의과대학 소아과학교실) ;
  • 이주원 (고려대학교 의과대학 소아과학교실)
  • Received : 2006.08.16
  • Accepted : 2006.09.13
  • Published : 2006.12.15

Abstract

Purpose : This study was conducted to compare the efficacy and safety of ibuprofen and indomethacin in the treatment of patent ductus arteriosus (PDA) in preterm infants and to determine whether ibuprofen can be an alternative drug. Methods : A total of 32 preterm infants with symptomatic PDA were enrolled in the study. Twelve infants received intravenous ibuprofen 10 mg/kg, followed by 5 mg/kg after 24 and 48 hours. As a comparative group, twenty premature infants received three doses of indomethacin 0.1-0.2 mg/kg every 12 hours. Results : PDA was closed in 11 of 12 infants of the ibuprofen group (92 percent) and in 18 of 20 infants of the indomethacin group (90 percent). Serum sodium concentration decreased along with time significantly (P<0.0001) and to its lowest level at 48 hours after administration of the third dose (P=0.0011) in both groups, but showed no significant difference between two groups. Serum BUN and creatinine concentrations were not changed significantly before or after treatment in each group and showed no difference between thetwo groups. The amount of urine output did not change along with time significantly in both groups (P=0.0725), and showed no significant difference between two groups. Conclusion : Ibuprofen has similar effects to indomethacin in the rate of PDA closure and complication when compared. It has similar changes in serum sodium level and complications when compared to indomethacin for the treatment of PDA in preterm infants. Therefore, intravenous ibuprofen may be used as an alternative agent in the treatment of symptomatic PDA in preterm infants.

목 적 : 미숙아 동맥관 개존 치료시 기존 치료제인 indomethacin 사용시 소변량 감소등의 부작용이 있으나 ibuprofen은 비슷한 효능을 보이면서도 부작용의 빈도는 낮다는 외국의 보고가 있어 국내에서는 처음으로 ibuprofen의 효능과 안전성에 대하여 알아보고자 본 연구를 시행하였다. 방 법 : 2005년 4월부터 2005년 12월까지 고려대학교 의료원 안산병원에서 출생한 재태연령 25주 이상 34주 미만의 미숙아 중 임상적 증상이 있는 동맥관 개존으로 진단되어 ibuprofen을 투여한 환아 12명과 2003년 2월부터 2005년 3월까지 같은 진단으로 indomethacin을 투여한 미숙아 중 임의로 20명을 선택하여 두 군으로 나누어 동맥관 개존의 치료 효과 및 약물의 부작용 및 임상 경과 등을 비교하였다. 결 과 : Ibuprofen 투여군에서 12례 중 11례(92%)에서 동맥관이 폐쇄되었고 indomethacin 투여군에서는 20례 중 18례(90%)에서 동맥관이 폐쇄되어 두 군간의 차이는 없었다(P=1.000). 혈청 나트륨 농도는 두 군 모두 투여시기에 따라 유의하게 감소하였으며(P<0.0001) 투여 전에 비해 3차 용량 투여 48시간 이후에 의미있게 감소하였다(P=0.0011). 혈청 BUN 및 creatinine 농도는 두 군 모두 약물 투여 전후에 차이가 없었으며 군간에서도 차이가 없었다. 소변 배설량도 두 군간 차이는 없었고 각 군별 투여시기에 따른 비교에서도 통계적으로 유의한 차이는 없었다(P=0.0725). 임상적 경과 및 주산기 합병증의 빈도는 두 군간 차이는 없었다. 결 론 : 정주용 ibuprofen은 미숙아 동맥관 개존의 치료에 있어서 정주 indomethacin과 비교할 때 폐쇄율과 합병증 빈도에서 비슷한 효과를 나타내었으나 혈청 나트륨 농도의 변화도 유사한 변화를 보이는 사실로 보아 indomethacin의 대안적인 약물로 사용할 수 있다고 생각한다.

Keywords

References

  1. Hammerman C. Patent ductus arteriosus. Clinical relevance of prostaglandins and prostaglandin inhibitors in PDA pathophysiology and treatment. Clin Perinatol 1995;22:457-79 https://doi.org/10.1016/S0095-5108(18)30293-8
  2. Farstad T, Bratlid D. Pulmonary effects of closure of patent ductus arteriosus in premature infants with severe respiratory distress syndrome. Eur J Pediatr 1994;153:903-5 https://doi.org/10.1007/BF01954743
  3. Wyllie J. Treatment of patent ductus arteriosus. Semin Neonatol 2003;8:425-32
  4. Clyman RI. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr 1996;128:601-7 https://doi.org/10.1016/S0022-3476(96)80123-5
  5. Merritt AT, Harris JP, Roghmann K, Wood B, Campanella V, Alexson C, et al. Early closure of the patent ductus arteriosus in very low-birth-weight infants: a controlled trial. J Pediatr 1981;99:281-9 https://doi.org/10.1016/S0022-3476(81)80479-9
  6. Fowlie PW, Davis PG. Prophylactic indomethacin for preterm infants: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2003;88:464-6 https://doi.org/10.1136/fn.88.6.F464
  7. Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants (Cochrane Review). In: The Cochrane Library, Oxford: Update Software, 2002, Issue 3. Art. No. CD000174
  8. Knight DB. The treatment of patent ductus arteriosus in preterm infants. A review and overview of randomized trials. Semin Neonatol 2001;6:63-73
  9. Van Bel F, Guit GL, Schipper J, van de Bor M, Baan J. Indomethacin-induced changes in renal blood flow velocity waveform in premature infants investigated with color Doppler imaging. J Pediatr 1991;118:621-6 https://doi.org/10.1016/S0022-3476(05)83391-8
  10. Lin YJ, Tsai YJ, Chen JS, Lin JS, Wu JM, Lin CH, et al. Renal effects and urinary excretion of prostaglandin following indomethacin therapy in premature infants with patent ductus arteriosus. Acta Paediatr Sin 1995;36:104-7
  11. Rennie JM, Doyle J, Cooke RW. Early administration of indomethacin to preterm infants. Arch Dis Child 1986;61: 233-8 https://doi.org/10.1136/adc.61.3.233
  12. Laudignon N, Chemtob S, Bard H, Aranda JV. Effect of indomethacin on the cerebral blood flow velocity of premature newborns. Biol Neonate 1988;54:254-62 https://doi.org/10.1159/000242860
  13. Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. J Pediatr 1999;135:733-8 https://doi.org/10.1016/S0022-3476(99)70093-4
  14. Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. 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 https://doi.org/10.1203/00006450-200001000-00009
  15. Kaplan BS, Restaino I, Raval DS, Gottlieb RP, Bernstein J. Renal failure in the neonate associated with in utero exposure to non-steroidal anti-inammatory agents. Pediatric Nephrology 1994;8:700-4. https://doi.org/10.1007/BF00869093
  16. Hardy P, Peri KG, Lahaie I, Varma DR, Chemtob S. Increased nitric oxide synthesis and action preclude choroidal vasoconstriction to hyperoxia in newborn pigs. Circulation Research 1996;79:504-11 https://doi.org/10.1161/01.RES.79.3.504
  17. Pellicer A, Aparicio M, Cabanas F, Valverde E, Quero J, Stiris TA. Effect of the cyclo-oxygenase blocker ibuprofen on cerebral blood volume and cerebral blood flow during normocarbia and hypercarbia in newborn piglets. Acta Pediatr 1999;88:82-8. https://doi.org/10.1080/08035259950170664
  18. Desfrere L, Zohar S, Morville P, Brunhes A, Chevret S, Pons G, et al. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J Clin Pharm Ther 2005;30:121-32 https://doi.org/10.1111/j.1365-2710.2005.00630.x
  19. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9 https://doi.org/10.1164/ajrccm.163.7.2011060
  20. Van Overmeire B, Chemtob S. The pharmacologic closure of the patent ductus arteriosus. Semin Fetal Neonatal Med 2005;10:177-84 https://doi.org/10.1016/j.siny.2004.10.003
  21. Choi BM. Trend in the management of patent ductus arteriosus in neonates. J Korean Pediatr Cardiol 2003;7(2 Suppl):177S-84S
  22. Yeh TF, Car I. Neonatal Therapeutics, 2nd ed. St Louis: Mosby Year Book, 1991;123?38
  23. Gersony WM, Peckham GJ, Ellison RC, Miettinen OS, Nadas AS. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr 1983;102:895-906. https://doi.org/10.1016/S0022-3476(83)80022-5
  24. Evans N. Current controversies in the diagnosis and treatment of patent ductus arteriosus in preterm infants. Adv Neonatal Care 2003;3:168-77 https://doi.org/10.1016/S1536-0903(03)00143-7
  25. Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants (Cochrane Review). In: The Cochrane Library, Oxford: Update Software, 2003, Issue 2. Art. No. CD004213.
  26. Kang NS, Yoo KH, Cheon H, Choi BM, Hong YS, Lee JW, et al. Indomethacin treatment decreases renal blood flow velocity in human neonates. Biol Neonate 1999;7:261-5
  27. Gournay V, Savagner C, Thiriez G, Kuster A, Roze JC. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002;359:1486-8. https://doi.org/10.1016/S0140-6736(02)08424-6
  28. Thomas RL, Parker GC, Van Overmeire B, Aranda JV. A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus. Eur J Pediatr 2005;164:135-40 https://doi.org/10.1007/s00431-004-1596-5
  29. Lago P, Bettiol T, Salvadori S, Pitassi I, Vianello A, Chiandetti L, 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;161:202-7. https://doi.org/10.1007/s00431-002-0915-y
  30. Zanardo V, Vedovato S, Lago P, Piva D, Faggian D, Chiozza L. Effects of ibuprofen and indomethacin on urinary antidiuretic hormone excretion in preterm infants treated for patent ductus arteriosus. Fetal Diagn Ther 2005;20:534-9 https://doi.org/10.1159/000088046
  31. Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, Degroote K, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000;343:674-81 https://doi.org/10.1056/NEJM200009073431001
  32. Van Overmeire B, Follens I, Hartmann S, Creten WL, Van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child Fetal Neonatal Ed 1997;76:179-84 https://doi.org/10.1136/fn.76.3.F179
  33. Supapannachart S, Limrungsikul A, Khowsathit P. Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi Hospital. J Med Assoc Thai 2002;85:1252-8.
  34. Su PH, Chen JY, Su CM, Huang TC, Lee HS. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Pediatr Int 2003;45:665-70 https://doi.org/10.1111/j.1442-200X.2003.01797.x
  35. Zanardo V, Vedovato S, Lago P, Trevisanuto D, Favaro F, Faggian D, et al. Urinary ET-1, AVP and sodium in premature infants treated with indomethacin and ibuprofen for patent ductus arteriosus. Pediatr Nephrol 2005;20:1552-6 https://doi.org/10.1007/s00467-005-2022-6
  36. 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: 549-54. https://doi.org/10.1016/S0022-3476(97)70060-X
  37. Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants (Cochrane Review). In: The Cochrane Library, Oxford: Update Software, 2005, Issue 4. Art. No. CD003481
  38. Van Overmeire B, Allegaert K, Casaer A, Debauche C, Decaluwe W, Jespers A, et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2004;364:1945-9 https://doi.org/10.1016/S0140-6736(04)17477-1
  39. Gournay V, Roze JC, Kuster A, Daoud P, Cambonie G, Hascoet JM, et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial. Lancet 2004;364:1939-44 https://doi.org/10.1016/S0140-6736(04)17476-X
  40. Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants(Cochrane Review). In: The Cochrane Library, Oxford: Update Software, 2006, Issue 1. Art. No. CD004213