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Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants

  • Review
  • Intervention

Authors


Abstract

Background

Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be achieved pharmacologically using cyclooxygenase inhibitors or by surgery. The efficacy of both treatment modalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterm infant, surgical ligation or treatment with indomethacin, has not been well established.

Objectives

To compare the effect of surgical ligation of PDA vs. medical treatment with cyclooxygenase inhibitors (using indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA.

Search methods

The standard search strategy of the Cochrane Neonatal Review Group was used. This included search of electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - July 2007), CINAHL (1982 - July 2007), EMBASE (1980 - July 2007); and hand search of abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002) or on line from May 2002 -July 2007. No language restrictions were applied.

Selection criteria

All trials 1) using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days) and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used as the initial treatment for closure of PDA.

Data collection and analysis

Assessment of methodological quality and extraction of data for included trials was undertaken independently by the authors. RevMan 4.1 was used for analysis of the data.

Main results

Only one study, trial B in the report of Gersony 1983, was found eligible. No additional studies were identified in the literature searches performed in July 2007. The trial compared the effect of surgical ligation of PDA vs. medical treatment with indomethacin, each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study found no statistically significant difference between surgical closure and indomethacin treatment in mortality during hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatinine level, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group in incidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] and retinopathy of prematurity stage III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2, 4)].

Authors' conclusions

The data regarding net benefit/harm are insufficient to make a conclusion as to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment for symptomatic PDA in preterm infants. It should be noted that three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment . It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes, as could the perioperative care.

摘要

背景

手術和以環氧化脢抑制劑用在有開放性動脈導管病症之早產兒上之比較

在早產兒的開放性動脈導管合併明顯的左側至右側分流會增加致病率及死亡率。可以藉由藥物如環氧化脢抑制劑或是手術及早關閉動脈導管。這兩種治療方法已經被證實是有效的。但是,在一開始治療有開放性動脈導管症狀的早產兒方面,用手術方式綁起來或是使用環氧化脢抑制劑,如indomethacin,哪一種方式比較好尚未有定論。

目標

比較在早產兒有症狀的開放性動脈導管,一開始使用手術將導管綁起來和使用藥物環氧化脢抑制劑(如 ndomethacin, ibuprofen, or mefenamic acid)在早產兒死亡率上效益的比較。

搜尋策略

應用了the Cochrane Neonatal Review Group的標準搜尋策略. 包括搜尋以下電子資料庫:Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007) EDLINE (1966年2007年7月), CINAHL (1982年  2007年7月), EMBASE (1980年  2007年7月);並手動搜尋小兒學會學術年會發表的摘要(1990年 2002年4月),或2002年5月 2007年7月之線上資料,並未採用語言限制

選擇標準

所有的試驗: 1)使用隨機和半隨機的方式選擇病人,2)病人為出生周數小於37週之早產兒或小於2500公克之低體重兒在新生兒時期(28天內)合併有症狀之開放性動脈導管,3)比較手術方式和藥物環氧合脢抑制劑做為一開始關閉導管治療之間的不同。

資料收集與分析

所收納的試驗之研究方法品質的評估及數據的擷取由各別作者獨立進行。數據係使用RevMan 4.1來作分析。

主要結論

只有一篇研究,Gersony 在1983年的B試驗是符合的。在2007年7月做的文獻搜尋沒有找到其他額外的研究。這個試驗是比較一開始使用手術關閉開放動脈導管和一開始使用藥物indomethacin的不同。此外,沒有其他的試驗在比較手術和其他的環氧化脢抑制劑如ibuprofen, mefenamic acid的不同。Gersony 1983年的B試驗包含了154個嬰兒。這篇研究發現在比較手術關閉和藥物indomethacin治療在住院死亡率,慢性肺疾病,出血,壞死性腸炎,敗血症,肌酐酸數值,及腦室出血等方面,沒有統計上的意義。只有在手術的族群發現有統計意義上的增加氣胸的機率,[RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] 以及增加早產兒視網膜病變第3、4期的機率。[RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% C, 50]但在關閉導管的失敗率上,手術的族群在統計上有意義的低於使用藥物indomethacin的族群。[RR 0.04 (95% CI 0.01, 0.27); RD −0.32 (95% CI −0.43, −0.21), NNT 3 (95% CI 2, 4)]。

作者結論

益處與壞處的資料不足以提供結論以決定手術關閉或是藥物indomethacin治療來作為關閉早產兒有症狀的開放性動脈導管的最初治療選擇。還有其他值得注意的是最近有3個研究指出手術關閉開放性動脈導管和增加慢性肺疾病,早產兒視網膜病變,神經感覺方面的障礙的機率有關。這可能和等待轉去有能力執行手術機構的時間有關,並因而影響到不良的預後。而也有可能和手術前後的照顧有關聯。

翻譯人

本摘要由高雄醫學大學附設醫院陳延珊翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

新生兒的血液一出生立即就進行循環交換。單早產兒還保留介於肺部的大血管和攜帶氧氣去身體其他部位的大血管之間的開口(開放性動脈導管,PDA)。當臨床症狀發生時,早期症狀治療開放性動脈導管可以幫助降低依賴人工呼吸器的時間,降低慢性肺疾病的機率,減少腸胃道的發炎破壞(像壞死性腸炎)的發生。一般常規的治療包含限制水分,利尿劑和環氧化脢抑制劑如indomethacin 或 ibuprofen。如果藥物治療無效再採用手術的方式關閉。只有一個隨機對照的研究可以被納進這篇回顧評論(其中包含154個需要呼吸支持的早產兒)。indomethacin和手術有一樣的效益。而這當中針對住院死亡率,慢性肺疾病,壞死性腸炎,腦部或其他出血在這兩種方法沒有任何差異。手術的方式在關閉動脈導管方面比較有效(治療三人即有一人獲益),但是它也和一些併發症如氣胸和早產兒視網膜病變有關。上述結果已經是在20多年前進行的研究內容。 臨床的操作及訓練已經改變的很多,手術方式關閉開放性動脈導管也更安全。 因此,此研究結果是否適用於現在仍是有爭議的。在2007年7月的這篇回顧的更新沒有找到其他額外的隨機對照試驗,但是3 個觀察研究顯示手術關閉開放性動脈導管增加的以下的危險性 ; 慢性肺疾病,早產兒視網膜病變和神經感覺系統的缺損。

Plain language summary

Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants

The way an infant's blood is circulated changes soon after birth. Initially, premature infants have an opening (a patent ductus arteriosus, PDA) between the large blood vessel to the lungs and the large blood vessel that carries oxygenated blood to the rest of the body. Early symptomatic treatment of PDA, when clinical signs first appear, helps reduce the amount of time an infant needs assisted breathing (mechanical ventilation) and the likelihood of chronic lung disease and damaging inflammation of the gut (necrotizing enterocolitis). Standard therapy includes restricting fluids, diuretics, and cyclooxygenase inhibitors like indomethacin or ibuprofen. The PDA is closed surgically if these medical treatments do not work. Only one randomised controlled study could be included in this review (including 154 preterm infants that needed breathing support). Indomethacin and surgery gave similar benefits. There were no differences in deaths during the hospital stay, chronic lung disease, necrotizing enterocolitis, cerebral or other bleeding. Surgery was more effective in closing the PDA (three needed to treat for one to benefit) but it was associated with complications (pneumothorax and retinopathy of prematurity). The one study found was carried out over 20 years ago. Clinical practice has changed a great deal and surgical closure of a PDA is safer. Therefore, whether the results of the study are applicable today is debatable. An update of this review in July 2007 did not identify any additional randomised controlled studies for inclusion, but three observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment .

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