Furosemide for prevention of morbidity in indomethacin-treated infants with patent ductus arteriosus

  • Review
  • Intervention




Inhibition of prostaglandin synthesis mediates closure of the ductus arteriosus and renal side effects after indomethacin administration. Because furosemide increases prostaglandin production, it could potentially help prevent indomethacin-related toxicity, but also decrease ductal response to indomethacin.


The primary objectives of this review were to assess (1) whether furosemide affects the incidence of failure of ductal closure after indomethacin and that of indomethacin-related toxicity and (2) the effect of furosemide on mid-term and long-term outcome. The secondary objective was to determine whether the effect of furosemide on renal function and water balance depends on prior extracellular volume (assessed by blood urea nitrogen [BUN]/creatinine ratio).

Search methods

Electronic databases (MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) and selected abstract books, without language restriction were searched. For the latest update, database searches were done on April 1, 2007 and Issue 1, 2007 of The Cochrane Library.

Selection criteria

Studies with (1) random allocation to either indomethacin alone or indomethacin and furosemide and (2) analysis of either short-term risk-benefit ratio of furosemide, mid- or long-term outcome, or the relationship between extracellular volume at study entry and changes in renal function were selected.

Data collection and analysis

Studies were assessed for possible bias and for quality of assessment of ductal patency. Categorical variables were assessed using relative risk and absolute risk reduction. The effects of furosemide on renal function and fluid balance were assessed by comparing changes from baseline in the treatment group with those in controls. Subsets were determined a priori based on BUN/creatinine ratio at study entry.

Main results

All three studies fulfilling the entry criteria had limitations, including possible or definite bias. There was substantial heterogeneity among studies.
Furosemide administration did not significantly increase the risk of failure of ductal closure; however, sample size was insufficient to rule out even a 31% increase. In the subset with initial BUN/creatinine ratio > 20 mg/mg, two of 18 patients receiving furosemide could not complete a three-dose course of indomethacin because of toxicity. Minimal or no information was available about any of the other main outcome variables. Furosemide increased urine output regardless of the initial BUN/creatinine ratio, leading to a 5% weight loss during a three-dose course, an undesired effect in patients with initial BUN/creatinine ratio > 20 mg/mg. Furosemide increased creatinine clearance only in patients with initial BUN/creatinine ratio < 20 mg/mg.

Authors' conclusions

There is not enough evidence to support the administration of furosemide to premature infants treated with indomethacin for symptomatic patent ductus arteriosus. Furosemide appears to be contraindicated in the presence of dehydration in those infants.




給予indomethacin會抑制前列腺素 (prostaglandin) 生成,此與開放性動脈導管關閉和腎臟副作用有關。因為furosemide會增加前列腺素製造,它可能潛在性可以幫助預防indomethacin相關毒性,但也會減少開放性動脈導管對indomethacin的反應。


此篇回顧文章主要目的是要評估: (1) furosemide是否會影響indomethacin關閉開放性動脈導管的發生率及其相關毒性; (2) furosemide對中期及長期預後的影響。第二個目的為決定furosemide對腎功能和水平衡的影響是否乃依據細胞外容積 (以血中尿素氮[BUN]和血清肌酸酐[creatinine]的比值來評估) 。


用不限定特定語言來搜尋電子醫學資料 (MEDLINE, EMBASE, CENTRAL, Cochrane圖書館) 和摘要書籍。對最新文獻的搜尋,是以2007年4月1日和2007年第一期的Cochrane圖書館為止。


納入選擇的研究包括 (1) 經由隨機分配而分組為單獨使用indomethacin或indomethacin加furosemide治療; (2) 分析furosemide的短期風險利益比、中長期預後、或和細胞外容積和腎功能變化關係相關的研究。


研究也評估可能的誤差和動脈導管通暢性評估的品質。利用相對危險因子和絕對危險因子減少來評估類別差異。Furosemide對腎功能和水平衡的效果,是以治療組基礎值的改變和控制組來比較。以試驗開始前的尿素氮和血清肌酸酐的比值 (BUN/creatinine) 為參考基礎。


納入討論的三個研究皆有其限制,包括可能或確定的偏差。此些研究相互間也有差異。Furosemide注射並不會明顯增加動脈導管關閉的失敗機率,然而因為樣本數過小,甚至不能偵測31% 的增加變化。在BUN/creatinine比率大於20mg/mg的病人組,因為藥物毒性關係,18人其中有2位病人無去接受完整三個indomethacin療程。極少或沒有資料顯示其他影響預後的變數。不管起始BUN/creatinine比值多寡,furosemide皆會增加尿量;注射三個劑量會造成體重減少5% ,這是起始BUN/creatinine比值超過20mg/mg的病人所不樂見的副作用。只有起始BUN/creatinine比值小於20mg/mg的病人,furosemide會增加肌酸酣廓清率 (creatinine clearance) 。





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


目前尚無強力證據顯示在已接受indomethacin治療的開放性動脈導管之早產兒常規使用furosemide (一種環利尿劑) 有益處。動脈導管是胎兒在胎內時期循環所必需,足月兒於出生不久後即關閉。早產嬰兒若出生後動脈導管未關閉,可能會發生症狀。這些有開放性動脈導管症狀的早產兒可接受indomethacin治療以求關閉動脈導管。Indomethacin可能會降低腎臟功能和尿量。Furosemide為可減少體內水份的利尿藥物,可能可以減低indomethacin對腎臟的不良作用。此篇回顧文章分析furosemide對接受indomethacin來關閉開放性動脈導管的早產兒之效果。結果發現沒有足夠的證據支持常規使用furosemide在已使用indomethacin治療的開放性動脈導管之早產兒。

Plain language summary

Furosemide for prevention of morbidity in indomethacin-treated infants with patent ductus arteriosus

There is no strong evidence of benefit from routine use furosemide, a loop diuretic, in preterm babies receiving indomethacin for treatment of patent ductus arteriosus. A blood vessel (ductus arteriosus), which is required for blood circulation for the fetus in the womb, closes soon after birth in babies born around the expected date of delivery (term infants). Babies born early (preterm) may develop symptoms if they do not close that blood vessel after birth. Preterm infants who have symptoms due to the ductus arteriosus may receive therapy (indomethacin) for closing that vessel. Indomethacin may decrease kidney function and the amount of urine. Furosemide, a medication which reduces body water (diuretic), might help limit the effects of indomethacin on the kidney. This review analyzed the effects of furosemide on preterm babies receiving indomethacin to close the ductus arteriosus. The review of trials found not enough evidence to recommend routine use of furosemide in preterm infants who receive indomethacin for closing a ductus arteriosus.