口服布洛芬治疗新生儿动脉导管未闭的对照研究

doi:10.3877/cma.j.issn.1673-5250.2013.02.011

目的

探讨新生儿动脉导管未闭(patent ductus arteriosus，PDA)的自然关闭率及口服布洛芬干预的利弊。

方法

选择2008年10月至2011年9月因"早产儿/新生儿肺炎、发绀"入院，生后15 h～24 d经心脏彩超确诊为PDA的患儿96例为研究对象。将其按照治疗方式的不同分为治疗组[n＝61，确诊后立即给予布洛芬混悬液口服治疗，首剂为10 mg/kg，24 h，48 h后再分别给予5 mg/kg；治疗(72～96)h后复查心脏彩超]，安慰剂组[n＝35，确诊后立即给予生理盐水口服，首剂为1 mL/kg，24 h，48 h后再分别给予0.5 mL/kg；(72～96)h后复查心脏彩超。对仍存在PDA的患儿，则按照治疗组方案治疗，(72～96)h后再复查心脏彩超](本研究遵循的程序符合本院人体试验委员会制定的伦理学标准，得到该委员会批准，分组征得受试对象监护人的知情同意，并与其签署临床研究知情同意书)。两组患儿一般临床资料及治疗前彩超检查结果比较，差异无统计学意义(P>0.05)。对两组治疗后复查心脏彩超结果及不良反应发生率进行统计学分析。

结果

①治疗组全部患儿，治疗组足月儿、非症状性PDA儿、不合并其他心脏病患儿、出生72 h内确诊为PDA患儿的动脉导管关闭率(分别为88.5%，91.3%，92.9%，89.6%及93.0%)均显著高于安慰剂组的同类患儿(62.9%，50.0%，68.0%，60.7%及66.7%)，差异均有统计学意义(P<0.05)；治疗组早产儿、症状性PDA儿、合并其他心脏病患儿、出生72 h后确诊为PDA患儿的动脉导管关闭率(分别为86.8%，78.9%，84.6%及77.8%)分别与安慰剂组的同类患儿(71.4%，50.0%，71.4%及50.0%)比较，差异均无统计学意义(P>0.05)。②两组早产儿与足月儿、症状性与非症状性PDA患儿、合并其他心脏病与不合并其他心脏病患儿、出生72 h内确诊与出生72 h后确诊的PDA患儿的动脉导管关闭率组内比较，差异均无统计学意义(P>0.05)。③安慰剂组第1次复查心脏彩超的结果显示，动脉导管关闭率为62.9%(22/35，均自发性关闭)，第2次则为61.5%(8/13，在治疗后关闭)。④4例早产儿出生10 d后接受布洛芬治疗，2例动脉导管关闭，2例导管内径缩小。⑤治疗过程中出现少尿，治疗组为6例(9.8%)，安慰剂组为2例(5.7%)。⑥未完成治疗/临床病历资料不完整的接受布洛芬治疗患儿中，出现血小板(PLT)严重下降、上消化道出血及便血各1例。

结论

口服布洛芬不但可有效促进出生10 d内的PDA早产儿动脉导管闭合，对于足月儿肺炎/发绀伴PDA及出生10 d后PDA早产儿的动脉导管闭合亦有效，而且临床应用相对安全。

关键词: 布洛芬, 动脉导管未闭, 婴儿，新生

Objective

To investigate rate of spontaneous closure, efficacy and safety of oral ibuprofen on neonatal patent ductus arteriosus (PDA).

Methods

From October 2008 to September 2011, a total of 96 neonates admitted to department of pediatrics with premature infants, neonate pneumonia or cyanosis associated with PDA confirmed by echocardiography from 15 h to 24 d after delivery. They were divided into two groups based on different treatment strategies: Treatment group (n=61, treatment by oral ibuprofen suspension 10 mg/kg, 5 mg/kg at 24 h and 48 h, respectively, and echocardiography examination after treatment 72 h to 96 h); placebo group (n=35, treatment by oral physiological saline 1 mL/kg, 0.5 mL/kg at 24 h and 48 h, respectively, echocardiography examination after treatment 72 h to 96 h. They were treatment by oral ibuprofen suspension as strategies of treatment group if PDA persistence, and echocardiography examination again after treatment by ibuprofen 72 h to 96 h. There had no significance difference between two groups among general clinical data and results of echocardiography of heart before treatment etc.(P>0.05). Data of reexamine results of echocardiography of heart and incidence of adverse reactions were analysis between two groups by statistics. Informed consent was obtained from the parents of each participating neonate.

Results

①The PDA closing rates of overall, full term infants, asymptomatic infants, without others cardiopathy infants, PDA confirmed born within 72 h in treatment group (88.5%, 91.3%, 92.9%, 89.6%, 93.0%) were significant higher than those in placebo group (62.9%, 50.0%, 68.0%, 60.7%, 66.7%)(P<0.05). There were no significant difference in PDA closing rates of preterm infants, symptomatic infants, with other cardiopathy infants, PDA confirmed born after 72 h between treatment group (86.8%, 78.9%, 84.6%, 77.8%) and placebo group (71.4%, 50.0%, 71.4%, 50.0%)(P>0.05). ②There were no significant difference between two groups in closing rates of PDA of preterm infants and full term infants, symptomatic and asymptomatic, with and without others cardiopathy, PDA confirmed born within and after 72 h (P>0.05). ③ In placebo group, PDA disappear spontaneously in 22/35 (62.9%) cases after treatment by placebo, and PDA were closed in 8/13 (61.5%) cases after treatmen by strategies as that of treatment group.④There were 4 cases premature infants born after 10 d treatment by ibuprofen, closed in 2/4 cases, and diameter reduced in the other 2/4 cases.⑤Oliguria occurred in 6 cases (9.8%) in treatment group, and 2 cases (5.7%) in placebo group. ⑥Another 3 cases treatment by ibuprofen who had been excluded by this study, occurred serious decrease of platelet (PLT), upper gastrointestinal hemorrhage, and hematochezia one case, respectively.

Conclusions

Oral ibuprofen is effective in closing PDA in preterm infants within 10 days of life. It is effective in closing PDA in full term infants with neonate pneumonia or cyanosis and preterm infants after 10 days of life, too. It is safe to clinical use.

Key words: ibuprofen, patent ductus arteriosus, infant, newborn

表1 96例PDA新生儿一般临床资料比较(±s)

Table 1 Comparison of general clinical data among 96 cases PDA neonates (±s)

组别	n	性别[n(%)]					Apgar评分(分)
组别	n	男性	女性	胎龄(孕周)	出生体重(g)	早产儿比例[n(%)]	1 min	5 min	合并其他心脏病比例[n(%)]
治疗组	61	33(54.1)	28(45.9)	36.5±2.9	2761±730	38(62.3)	7.2±1.3	8.6±0.6	13(21.3)
安慰剂组	35	19(54.3)	16(45.7)	36.6±3.0	2577±586	21(60.0)	7.7±1.2	8.8±0.7	7(20.0)
χ²/t		0.000		－0.149	1.273	0.049	－1.627	－0.977	0.023
P		0.986		0.882	0.206	0.824	0.107	0.331	0.879

表1 96例PDA新生儿一般临床资料比较(±s)

Table 1 Comparison of general clinical data among 96 cases PDA neonates (±s)

组别	n	性别[n(%)]					Apgar评分(分)
组别	n	男性	女性	胎龄(孕周)	出生体重(g)	早产儿比例[n(%)]	1 min	5 min	合并其他心脏病比例[n(%)]
治疗组	61	33(54.1)	28(45.9)	36.5±2.9	2761±730	38(62.3)	7.2±1.3	8.6±0.6	13(21.3)
安慰剂组	35	19(54.3)	16(45.7)	36.6±3.0	2577±586	21(60.0)	7.7±1.2	8.8±0.7	7(20.0)
χ²/t		0.000		－0.149	1.273	0.049	－1.627	－0.977	0.023
P		0.986		0.882	0.206	0.824	0.107	0.331	0.879

表2 96例PDA新生儿治疗前心脏彩超检查结果比较(±s)

Table 2 Comparison of results of echocardiography before treatment among 96 cases PDA neonates (±s)

组别	n	彩超确诊时患儿日龄(d)^a	导管直径(mm)^a	导管直径的平方/出生体重(mm²/kg)^a	导管水平左向右分流峰值流速(m/s)^b	导管两端压差(mm Hg)^b	闻及2/6级及以上收缩期杂音比例[n(%)]	脉压差(mm Hg)^b
治疗组	61	2.0(2.0～4.0)	2.0(2.0～2.0)	1.5(1.2～2.0)	2.4±0.8	25.3±14.6	23(37.7)	19.7±6.4
安慰剂组	35	3.0(2.0～3.0)	2.0(2.0～2.0)	1.7(1.3～2.7)	2.3±0.8	22.6±15.0	12(34.3)	20.9±6.9
z/t		－0.153	－0.794	－1.123	0.682	0.853	χ²＝0.112	0.904
P		0.878	0.427	0.261	0.497	0.396	0.738	0.368

表2 96例PDA新生儿治疗前心脏彩超检查结果比较(±s)

Table 2 Comparison of results of echocardiography before treatment among 96 cases PDA neonates (±s)

组别	n	彩超确诊时患儿日龄(d)^a	导管直径(mm)^a	导管直径的平方/出生体重(mm²/kg)^a	导管水平左向右分流峰值流速(m/s)^b	导管两端压差(mm Hg)^b	闻及2/6级及以上收缩期杂音比例[n(%)]	脉压差(mm Hg)^b
治疗组	61	2.0(2.0～4.0)	2.0(2.0～2.0)	1.5(1.2～2.0)	2.4±0.8	25.3±14.6	23(37.7)	19.7±6.4
安慰剂组	35	3.0(2.0～3.0)	2.0(2.0～2.0)	1.7(1.3～2.7)	2.3±0.8	22.6±15.0	12(34.3)	20.9±6.9
z/t		－0.153	－0.794	－1.123	0.682	0.853	χ²＝0.112	0.904
P		0.878	0.427	0.261	0.497	0.396	0.738	0.368

表3 两组治疗(72～96)h后复查心脏彩超的动脉导管关闭率比较

Table 3 Comparison of results of the closing rates of ductus arteriosus during 72 h to 96 h after oral ibuprofen suspension therapy or placebo

组别	n	总关闭率[n(%)]	PDA早产儿	PDA足月儿	症状性PDA患儿	非症状性PDA患儿	合并其他心脏病患儿	不合并其他心脏病患儿	出生72 h内确诊患儿	出生72 h后确诊患儿
治疗组	61	154(88.5)	86.8%(33/38)	91.3%(21/23)	78.9%(15/19)	92.9%(39/42)	84.6%(11/13)	89.6%(43/48)	93.0%(40/43)	77.8%(14/18)
安慰剂组	35	22(62.9)	71.4%(15/21)	50.0% ( 7/14)	50.0% ( 5/10)	68.0%(17/25)	71.4% ( 5/ 7)	60.7%(17/28)	66.7%(18/27)	50.0% ( 4/ 8)
Pearson χ²/Continuity
Correction χ²		8.884	1.224	5.978	－	5.368	－	8.868	6.362	－
P		0.003	0.269	0.014	Fisher's ExactTest 0.205	0.021	Fisher's ExactTest 0.587	0.003	0.012	Fisher's ExactTest 0.197

表3 两组治疗(72～96)h后复查心脏彩超的动脉导管关闭率比较

Table 3 Comparison of results of the closing rates of ductus arteriosus during 72 h to 96 h after oral ibuprofen suspension therapy or placebo

组别	n	总关闭率[n(%)]	PDA早产儿	PDA足月儿	症状性PDA患儿	非症状性PDA患儿	合并其他心脏病患儿	不合并其他心脏病患儿	出生72 h内确诊患儿	出生72 h后确诊患儿
治疗组	61	154(88.5)	86.8%(33/38)	91.3%(21/23)	78.9%(15/19)	92.9%(39/42)	84.6%(11/13)	89.6%(43/48)	93.0%(40/43)	77.8%(14/18)
安慰剂组	35	22(62.9)	71.4%(15/21)	50.0% ( 7/14)	50.0% ( 5/10)	68.0%(17/25)	71.4% ( 5/ 7)	60.7%(17/28)	66.7%(18/27)	50.0% ( 4/ 8)
Pearson χ²/Continuity
Correction χ²		8.884	1.224	5.978	－	5.368	－	8.868	6.362	－
P		0.003	0.269	0.014	Fisher's ExactTest 0.205	0.021	Fisher's ExactTest 0.587	0.003	0.012	Fisher's ExactTest 0.197

表4 治疗组4例PDA早产儿生后10 d予布洛芬治疗的一般临床资料比较

Table 4 Comparison of general clinical data among 4 cases PDA preterm infants born after 10 d treatment by ibuprofen

No.	胎龄(孕周)	出生体重(g)	Apgar评分(分)		治疗时日龄(d)	治疗前导管内径(mm)	治疗后导管内径(mm)	导管直径的平方/出生体重(mm²/kg)	导管水平左向右分流峰值流速(m/s)	导管两端压差(mm Hg)	肌钙蛋白I (μg/L)	闻及2/6级及以上收缩期杂音	脉压差(mm Hg)
No.	胎龄(孕周)	出生体重(g)	1 min	5 min	治疗时日龄(d)	治疗前导管内径(mm)	治疗后导管内径(mm)	导管直径的平方/出生体重(mm²/kg)	导管水平左向右分流峰值流速(m/s)	导管两端压差(mm Hg)	肌钙蛋白I (μg/L)	闻及2/6级及以上收缩期杂音	脉压差(mm Hg)
1	28^＋4	1200	3	8	11	2.0	0.0	3.3	1.73	25	0.10	否	17
2	29	1450	6	8	22	2.0	0.0	2.8	3.20	41	0.05	是	29
3	31^＋3	1300	7	7	24	3.5	1.0	9.4	2.94	34	0.03	是	10
4	31^＋4	1750	8	9	12	2.0	1.0	2.3	1.28	18	0.04	否	26

表4 治疗组4例PDA早产儿生后10 d予布洛芬治疗的一般临床资料比较

Table 4 Comparison of general clinical data among 4 cases PDA preterm infants born after 10 d treatment by ibuprofen

No.	胎龄(孕周)	出生体重(g)	Apgar评分(分)		治疗时日龄(d)	治疗前导管内径(mm)	治疗后导管内径(mm)	导管直径的平方/出生体重(mm²/kg)	导管水平左向右分流峰值流速(m/s)	导管两端压差(mm Hg)	肌钙蛋白I (μg/L)	闻及2/6级及以上收缩期杂音	脉压差(mm Hg)
No.	胎龄(孕周)	出生体重(g)	1 min	5 min	治疗时日龄(d)	治疗前导管内径(mm)	治疗后导管内径(mm)	导管直径的平方/出生体重(mm²/kg)	导管水平左向右分流峰值流速(m/s)	导管两端压差(mm Hg)	肌钙蛋白I (μg/L)	闻及2/6级及以上收缩期杂音	脉压差(mm Hg)
1	28^＋4	1200	3	8	11	2.0	0.0	3.3	1.73	25	0.10	否	17
2	29	1450	6	8	22	2.0	0.0	2.8	3.20	41	0.05	是	29
3	31^＋3	1300	7	7	24	3.5	1.0	9.4	2.94	34	0.03	是	10
4	31^＋4	1750	8	9	12	2.0	1.0	2.3	1.28	18	0.04	否	26

[1]	Kliegman RM, Behrman RE, Jenson HB, et al. Nelson textbook of pediatrics. 18th ed[M]. Philadelphia: Saunders Elsevier, 2007, 1891-1893, 731-741.
[2]	Hamrick SEG, Hansmann G. Patent ductus arteriosus of the preterm infant[J]. Pediatrics, 2010, 125:1020-1030.
[3]	Noori S, McCoy M, Friedlich P, et al. Failure of ductus arteriosus closure is associated with increased mortality in preterm infants[J]. Pediatrics, 2009, 123:e138-e144.
[4]	Chorne N, Leonard C, Piecuch R, et al. Patent ductus arteriosus and its treatment as risk factors for neonatal and neurodevelopmental morbidity[J]. Pediatrics, 2007, 119:1165-1174.
[5]	Van Overmeire B, Allegaert K, Casaer A, et al. Prophylactic ibuprofen in premature infants: A multicentre, randomised, double-blind, placebo-controlled trial[J]. Lancet, 2004, 364:1945-1949.
[6]	Lemmers PMA, Toet MC, Bel F. Impact of patent ductus arteriosus and subsequent therapy with indomethacin on cerebral oxygenation in preterm infants[J]. Pediatrics, 2008, 121:142-147.
[7]	Tacy TA. Abnormalities of the ductus arteriosus and pulmonary arteries//Lai WL, Mertens LL, Cohen MS, et al. Echocardiography in pediatric and congenital heart disease[M]. West Sussex, United Kingdom: Wiley-Blackwell, 2009, 283-296.
[8]	MalviyaMN, Ohlsson A, Shah SS. Surgical versus medical treatment with cyclooxygenase inhibitors for symp tomatic patent ductus arteriosus in preterm infants[J]. Cochrane Database Systemat Rev, 2008, CD003951.
[9]	Bhandari V, Zhou G, Bizzarro MJ, et al. Genetic contribution to patent ductus arteriosus in the premature newborn[J]. Pediatrics, 2009, 123:669-673.
[10]	Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus[J]. N Engl J Med, 2000, 343:674-681.
[11]	Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants[J]. Cochrane Database Syst Rev, 2010, 14:CD003481.
[12]	Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus[J]. N Engl J Med, 2000, 343:674-681.
[13]	Gournay V, Savagner C, Thiriez G, et al. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants[J]. Lancet, 2002, 359:1486-1488.
[14]	Gournay V, Roze JC, Kuster A, et al. Prophylactic ibuprofen versus placebo in very premature infants:A randomised, doubleblind, placebo-controlled trial[J]. Lancet, 2004, 364:1939-1944.
[15]	Mosca F, Bray M, Stucchi I, et al. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants[J]. Lancet, 2002, 360:1023-1024.
[16]	Cherif A, Khrouf N, Jabnoun S, et al. Randomized pilot study comparing oral ibuprofen with intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus[J]. Pediatrics, 2008, 122:e1256-e1261.
[17]	Erdeve O, Yurttutan S, Altug N, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: A randomised controlled trial in extremely low birthweight infants[J]. Arch Dis Child Fetal Neonatal Ed, 2012, 97(4):F279-283.
[18]	Jiang Y, Gao XY, Gu CS, et al. Indomethacin therapy for patent ductus arteriosus (PDA) in newborn infants: A clinical observation[J]. J Neonatol, 2003, 18:12-14.
[19]	Feng Q, Li Y, Wang Y, et al. Clinical investigation on patent ductus arteriosus of premature Infants[J]. J Appl Clin Pediatr, 2005, 20:129-131.
[20]	Koch J, Hensley G, Roy L, et al. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less[J]. Pediatrics, 2006, 117:1113-1121.
[21]	Dagle JM, Lepp NT, Cooper ME, et al. Determination of genetic predisposition to patent ductus arteriosus in preterm infants[J]. Pediatrics, 2009, 123:1116-1123.
[22]	Kajino H, Chen YQ, Seidner SR, et al. Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling[J]. Am J Physiol Regul Integr Comp Physiol, 2001, 281:R291-301.
[23]	McCurnin D, Clyman RI. Effects of a patent ductus arteriosus on postprandial mesenteric perfusion in premature baboons[J]. Pediatrics, 2008, 122:e1262-e1267.
[24]	Noori S, McCoy M, Friedlich P, et al. Failure of ductus arteriosus closure is associated with increased mortality in preterm infants[J]. Pediatrics, 2009, 123:e138-e144.
[25]	Van Overmeire B, Van de Broek H, Van Laer P, et al. Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with resp iratory distress syndrome[J]. J Pediatr, 2001, 138:205-211.

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[7]	赵金琦, 杨楠, 宫丽霏, 唐玥, 李璐璐, 杨海河, 孔元原. 2011—2020年北京市小于胎龄儿出生状况分析[J]. 中华妇幼临床医学杂志(电子版), 2023, 19(03): 278-286.
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[12]	郝萧, 刘兴莉, 夏小叶, 刁雪芹, 姚美雪. 母亲免疫球蛋白G不规则抗体效价及其效价积分对母婴Rh血型不合新生儿溶血病患儿换血治疗的预测分析[J]. 中华妇幼临床医学杂志(电子版), 2022, 18(06): 677-684.
[13]	张非红, 夏斌. 肠道菌群失调与新生儿坏死性小肠结肠炎发病机制的研究现状[J]. 中华妇幼临床医学杂志(电子版), 2022, 18(05): 523-527.
[14]	鄢锦丽, 陈大鹏. 益生菌在新生儿呼吸系统疾病临床治疗中的研究现状[J]. 中华妇幼临床医学杂志(电子版), 2022, 18(05): 517-522.
[15]	强光峰, 孟兰兰, 赵静, 牛峰海, 任雪云. 肺部超声评分对呼吸困难新生儿使用有创机械通气的预测价值[J]. 中华诊断学电子杂志, 2023, 11(02): 104-108.

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