Neonatal Medicine

The Korean Society of Neonatology (대한신생아학회)
권호 표지

Predictors of Failed Closure of Patent Ductus Arteriosus with the First Course of Indomethacin in Preterm Infants

미숙아 동맥관 개존에서 인도메타신 1차 투여 후 폐쇄 실패의 예측 인자

  • Lee, Mong-Young (Aideul Pediatric Clinic) ;
  • Lim, Dong-Hee (Department of Pediatrics, Korea University, School of Medicine) ;
  • Park, Kyu-Hee (Department of Pediatrics, Korea University, School of Medicine) ;
  • Ha, Gi-Su (Department of Pediatrics, Korea University, School of Medicine) ;
  • Lee, Jang-Hoon (Department of Pediatrics, Korea University, School of Medicine) ;
  • Choi, Byung-Min (Department of Pediatrics, Korea University, School of Medicine) ;
  • Hong, Young-Sook (Department of Pediatrics, Korea University, School of Medicine) ;
  • Yoo, Kee-Hwan (Department of Pediatrics, Korea University, School of Medicine) ;
  • Lee, Joo-Won (Department of Pediatrics, Korea University, School of Medicine)
  • 이몽영 (아이들 소아청소년과) ;
  • 임동희 (고려대학교 의과대학 소아과학교실) ;
  • 박규희 (고려대학교 의과대학 소아과학교실) ;
  • 하기수 (고려대학교 의과대학 소아과학교실) ;
  • 이장훈 (고려대학교 의과대학 소아과학교실) ;
  • 최병민 (고려대학교 의과대학 소아과학교실) ;
  • 홍영숙 (고려대학교 의과대학 소아과학교실) ;
  • 유기환 (고려대학교 의과대학 소아과학교실) ;
  • 이주원 (고려대학교 의과대학 소아과학교실)
  • Published : 2010.05.31
⟨ Previous Next ⟩

Abstract

Purpose : This study was performed to determine the predictors of failed closure of a patent ductus arteriosus (PDA) following the first course of indomethacin in symptomatic preterm infants. Methods : Forty three of 43 preterm infants, admitted to the neonatal intensive care unit diagnosed with PDA and treated with indomethacin at the Korea University Medical Center between January 1990 and October 2007, ware studied. The perinatal risk factors affecting the failed closure of PDA were retrospectively assessed. Results : The failed PDA closure group included 16 (37%) out of 43 infants three of whom underwent surgery. The closure group included 27 (63%) out of 43 infants. In the failed closure group, the Apgar scores (1 min, 5 min) were significantly higher (P<0.05) and antenatal steroid administration was significantly lower (P<0.05). In addition, dopamine administration was significantly lower (P<0.05) and the mean postnatal age at diagnosis was significantly lower (P<0.05). Multiple logistic regression for the prediction of failed PDA closure found only antenatal steroid administration (OR 0.092, CI 0,010-0.826, P=0.0331) as an associated factor. Conclusion : In patients with antenatal steroid administration the failed PDA closure rate was significantly lower. Therefore, antenatal steroid administration can be considered as an important factor for the closure of PDA in preterm pregnancies.

목 적 : 미숙아 동맥관 개존의 일차적인 치료제로 인도메타신이 효과적으로 쓰이지만 일부에서는 폐쇄 실패로 반복 투여나 수술적 치료를 필요로 한다. 동맥관 개존은 미숙아에서 높은 유병률, 사망률의 원인으로 내과적 치료가 실패 했을 경우 단락이 많으면 조기에 외과적 결찰을 고려해야 한다. 본 연구에서는 미숙아에서 동맥관개존에 대한 인도메타신의 1차 투여 후 치료 효과에 영향을 미치는 요인들을 분석하여 동맥관 개존 폐쇄 실패를 예측 할 수 있는 중요한 예측 인자를 알아보고 약물재투여 및 외과적 결찰이 필요한 환아를 조기에 선별 하여 대비함으로써 합병증을 최소화 하는데 도움이 되고자 하였다. 방 법: 1990년 1월부터 2007년 12월 사이 고려 대학교 의료원 신생아 중환자실에 입원 하였던 재태기간 37주 미만의 미숙아 중에서 동맥관 개존으로 진단되어 인도메타신을 투여 받았던 43명의 미숙아를 대상으로 하였다. 1차 투여 후 동맥관이 폐쇄된 27명을 폐쇄군으로, 폐쇄에 실패한 16명을 비폐쇄군으로 하여 두 군 간의 차이를 비교 분석하였으며 인도메타신 치료 효과에 영향을 줄 수 있는 인자들에 관하여 후향적으로 조사하였다. 결 과:대상 환아는 총 43명으로 남아 20명(46.5%), 여아 23명(53.5%) 이었다. 평균 아프가 점수는 폐쇄군이 1분에 4.1$\pm$2.1점, 5분에 6.1$\pm$1.9점이었고, 비폐쇄군은 1분에 5.4$\pm$1.7점, 5분에 7.3$\pm$1.2점으로 폐쇄군에서 통계적으로 유의하게 점수가 낮았다(P<0.04, P<0.03). 산전 스테로이드 투여를 받은 경우는 폐쇄군 16명(59.3%), 비폐쇄군 3명(18.8%)으로 폐쇄군에서 통계적으로 유의하게 높았다(P<0.01). 도파민 투여는 폐쇄군 17명(63.0%), 비폐쇄군 3명(18.8%)으로 폐쇄군에서 유의하게 높았다(P<0.01). 진단 시 연령은 폐쇄군 3.6$\pm$2.1일, 비폐쇄군 5.0$\pm$2.2일로 비폐쇄군에서 유의하게 높았다(P<0.05). 이들 주산기 인자 간의 다중로지스틱 회귀분석 결과 산전 스테로이드 투여만이(OR0.092, CI 0.010-0.826, P=0.0331) 동맥관 폐쇄 실패에 영향을 미치는 독립적인 인자로서 관련이 있었다. 결 론 : 본 연구에서는 산전 스테로이드를 투여 받은 산모에게서 출생한 미숙아에서 통계적으로 유의하게 동맥관 폐쇄 실패율이 낮게 나타났다. 그러므로 미숙아에 서 동맥관 개존 조기 진단과 함께 적극적인 산전 스테로이드 투여가 동맥관 개존 폐쇄 실패율을 낮추는 중요한 인자라 생각된다.

Keywords

References

  1. Clyman RI. Ibuprofen and patent ductus arteriosus. N Engl J Med 2000;343:728-30. https://doi.org/10.1056/NEJM200009073431009
  2. Hammerman C, Kaplan M. Comparative tolerability of pharmacological treatments for patent ductus arteriosus. Drug Saf 2001;24:537-51. https://doi.org/10.2165/00002018-200124070-00005
  3. Fanos V, Benini D, Verlato G, Errico G, Cuzzolin L. Efficacy and renal tolerability of ibuprofen vs. indomethacin inpreterm infants with patent ductus arteriosus. Fundam Clin Pharmacol 2005;19:187-93. https://doi.org/10.1111/j.1472-8206.2004.00314.x
  4. 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
  5. Aggarwal R, Bajpai A, Deorari AK, Paul VK. Patent ductus arteriosus in preterm neonates. Indian J Pediatr 2001;68:981-4. https://doi.org/10.1007/BF02722601
  6. 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
  7. 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
  8. Merritt TA, Harris JP, Roghmann K, Wood B, Campanella V, Alexson C, et al. Early closure of the patent ductus arteriosus in very lowbirth-weight infants: a controlled trial. J Pediatr 1981;99:281-6. https://doi.org/10.1016/S0022-3476(81)80479-9
  9. Lee JH, Lee SJ, Hong JS, Han HS, Park BS. Surgical ligation of the patent ductus arteriosus in very low birth weight premature infants: clinical comparison between indomethacin therapy and early surgical ligation. Chungbuk Med J 2000;10:150-8.
  10. Noori S, McCoy M, Friedlich P, Bright B, Gottipati V, Seri I, et al. Failure of ductus arteriosus closure is associated with increased mortality in preterm infants. Pediatrics 2009;123:e138-44. https://doi.org/10.1542/peds.2008-2418
  11. 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;138:205-11. https://doi.org/10.1067/mpd.2001.110528
  12. Drougia A, Giapros V, Krallis N, Theocharis P, Nikaki A, Tzoufi M, et al. Incidence andrisk factors for cerebral palsy in infants with perinatal problems: a 15-year review. Early Hum Dev 2007;83:541-7. https://doi.org/10.1016/j.earlhumdev.2006.10.004
  13. Moin F, Kennedy KA, Moya FR. Risk factors predicting vasopressor use after patent ductus arteriosus ligation. Am J Perinatol 2003;20:313-20. https://doi.org/10.1055/s-2003-42693
  14. Noori S, Friedlich P, Seri I, Wong P. Changes in myocardial function and hemodynamics after ligation of the ductus arteriosus in preterm infants. J Pediatr 2007;150:597-602. https://doi.org/10.1016/j.jpeds.2007.01.035
  15. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr 2007;150:229-34, 34e1. https://doi.org/10.1016/j.jpeds.2006.11.039
  16. Chorne N, Leonard C, Piecuch R, Clyman RI. Patent ductus arteriosus and its treatment as risk factors for neonatal and neurodevelopmental morbidity. Pediatrics 2007;119:1165-74. https://doi.org/10.1542/peds.2006-3124
  17. Clyman R, Cassady G, Kirklin JK, Collins M, Philips JB 3rd. The role of patent ductus arteriosus ligation in bronchopulmonary dysplasia: reexamining a randomized controlled trial. J Pediatr 2009;154:873-6. https://doi.org/10.1016/j.jpeds.2009.01.005
  18. Clyman RI, Seidner SR, Kajino H, Roman C, Koch CJ, Ferrara N, et al. VEGF regulates remodeling during permanent anatomic closure of the ductus arteriosus. Am J Physiol Regul Integr Comp Physiol 2002;282:R199-206. https://doi.org/10.1152/ajpregu.00298.2001
  19. Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR, et al. Permanent anatomic closure of the ductus arteriosus in newborn baboons: the roles of postnatal constriction, hypoxia, and gestation. Pediatr Res 1999;45:19-29. https://doi.org/10.1203/00006450-199901000-00005
  20. Narayanan M, Cooper B, Weiss H, Clyman RI. Prophylactic indomethacin: factors determining permanent ductus arteriosus closure. J Pediatr 2000;136:330-7. https://doi.org/10.1067/mpd.2000.103414
  21. Chorne N, Jegatheesan P, Lin E, Shi R, Clyman RI. Risk factors for persistent ductus arteriosus patency during indomethacin treatment. J Pediatr 2007;151:629-34. https://doi.org/10.1016/j.jpeds.2007.05.007
  22. Boo NY, Mohd-Amin I, Bilkis AA, Yong-Junina F. Predictors of failed closure of patent ductus arteriosus with indomethacin. Singapore Med J 2006;47:763-8.
  23. Costa S, Zecca E, De Luca D, De Carolis MP, Romagnoli C. Efficacy of a single dose of antenatal corticosteroids on morbidity and mortality of preterm infants. Eur J Obstet Gynecol Reprod Biol 2007;131:154-7. https://doi.org/10.1016/j.ejogrb.2006.05.006
  24. Eronen M, Kari A, Pesonen E, Hallman M. The effect of antenatal dexamethasone administration on the fetal and neonatal ductus arteriosus. A randomized double-blind study. Am J Dis Child 1993;147:187-92. https://doi.org/10.1001/archpedi.1993.02160260077026
  25. Clyman RI, Waleh N, Black SM, Riemer RK, Mauray F, Chen YQ. Regulation of ductus arteriosus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension, and vasa vasorum. Pediatr Res 1998;43:633-44. https://doi.org/10.1203/00006450-199805000-00012
  26. Shaffer CL, Gal P, Ransom JL, Carlos RQ, Smith MS, Davey AM, et al. Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus. Crit Care Med 2002;30:343-8. https://doi.org/10.1097/00003246-200202000-00013
  27. Supapannachart S, Khowsathit P, Patchakapati B. Indomethacin prophylaxis for patent ductus arteriosus(PDA) in infants with a birth weight of less than 1250 grams. J Med Assoc Thai 1999;82 Suppl 1:S87-92.
  28. Salhab WA, Hynan LS, Perlman JM. Partial or complete antenatal steroids treatment and neonatal outcome in extremely low birth weight infants < or =1000 g: is there a dose-dependent effect? J Perinatol 2003;23:668-72. https://doi.org/10.1038/sj.jp.7211007
  29. Tsai MY, Brown DM. Effect of dexamethasone on fetal lung 15-hydroxy-prostaglandin dehydrogenase: possible mechanism for the prevention of patent ductus arteriosus by maternal dexamethasone therapy. Prostaglandins Leukot Med 1987;27:237-45. https://doi.org/10.1016/0262-1746(87)90074-6
  30. Goldberg LI. Cardiovascular and renal actions of dopamine: potential clinical applications. Pharmacol Rev 1972;24:1-29.
  31. Cheung PY, Barrington KJ. Renal dopamine receptors: mechanisms of action and developmental aspects. Cardiovasc Res 1996;31:2-6. https://doi.org/10.1016/S0008-6363(95)00206-5
  32. Manoogian C, Nadler J, Ehrlich L, Horton R. The renal vasodilating effect of dopamine is mediated by calcium flux and prostacyclin release in man. J Clin Endocrinol Metab 1988;66:678-83. https://doi.org/10.1210/jcem-66-4-678
  33. Barrington K, Brion LP. Dopamine versus no treatment to prevent renal dysfunction in indomethacin-treated preterm newborn infants. Cochrane Database Syst Rev 2002;(3):CD003213.