口服消炎痛和布洛芬治疗早产儿动脉导管未闭的比较

目的：静脉注射消炎痛是早产儿动脉导管未闭的常规治疗方法,但治疗过程中常出现一些副作用,如少尿、消化道出血、脑血流灌注减少。近年来,静脉注射布洛芬已用于治疗早产儿动脉导管未闭。布洛芬治疗不会减少脑血流灌注,也不会影响胃肠道和肾脏的血流动力学。伊朗目前尚无消炎痛和布洛芬的静脉制剂供应。该研究旨在比较这两种药的口服制剂治疗早产儿动脉导管未闭的疗效和安全性。方法：36例胎龄小于34周经超声心动图确诊患有动脉导管未闭的早产儿被随机分为两组,每组18人。一组给予消炎痛口服,每次0.2 mg/kg,24 h给药 1 次,共3次。另一组给予布洛芬口服,共 3 次,间隔时间为24 h,首剂为 10 mg/kg,随后两次各 5 mg/kg。用药后观察导管闭合率、副作用、并发症及临床过程。结果：用药后布洛芬组18例患儿动脉导管都闭合（100％）,而消炎痛组18例中有15例患儿动脉导管闭合（83.3%）（P＞0.05）。两组疗效差异统计学无显著性意义。治疗前后两组的血清尿素氮和肌酐含量差异也无显著性意义。消炎痛组发生了3例（16.6%）坏死性小肠结肠炎,布洛芬组则无,差异有显著性意义 (P＜0.05)。治疗1个月后两组成活率均为 94%（17／18）。消炎痛组1例死于坏死性小肠结肠炎,布洛芬组1例死于败血症。结论：口服布洛芬治疗早产儿动脉导管未闭和口服消炎痛治疗一样有效,而且坏死性小肠结肠炎的发生率较口服消炎痛治疗低。［中国当代儿科杂志,2007,9（5）：399-403］     

Urinary aquaporin-2 excretion during ibuprofen or indomethacin treatment in preterm infants with patent ductus arteriosus

Aim: Water channel AQP2 is the target for vasopressin (AVP) and a major determinant of urinary concentrating capacity. In mature kidneys, prostaglandins counteract the effect of AVP on AQP2 expression at functional sites. We investigated whether disturbances in water homeostasis in infants with patent ductus arteriosus (PDA) treated with prostaglandin inhibitors can be attributed to activation of AQP2. Methods: In 53 infants with symptomatic PDA (gestational age 24–33 weeks), 30 receiving ibuprofen and 23 indomethacin starting at 2–15 days of life, clinical and biochemical data were collected before treatment and after each dose of the drugs. Urinary AQP2 was determined by dot immunoblotting. Results: Urinary AQP2 level and osmolality were decreased in both groups. Urinary osmolality was overall low and correlated inversely with fluid uptake. In ibuprofen group, there was no correlation of AQP2 level with urinary osmolality. Conclusion: There was no AQP2 upregulation in the infants. The low urinary osmolality and dissociation between urinary osmolality and urinary AQP2 level indicate that the fluid retention sometimes observed in PDA infants treated with prostaglandin inhibitors is not caused by increased levels of functional AQP2. Thus, knowledge about the renal physiology of the adult cannot always be transferred to the infant kidney.     

Patent ductus arteriosus in preterm neonates

Failure of the ductus arteriosus to close within 48–96 hours of postnatal age results in a left to right shunt across the ductus and overloading of the pulmonary circulation. This is more likely to happen in premature neonates with respiratory distress syndrome. Deterioration in the respiratory status on day 3–4 in a ventilated neonate and unexplained metabolic acidosis may be the earliest indicators of a patent ductus arteriosus (PDA). Indomethacin is the main stay of medical management of PDA in preterm neonates. Guidelines for administration of indomethacin have been described in the protocol. Restricted fluid therapy may be beneficial in the prevention of PDA in preterm neonates. Presence of PDA in a term neonate should be investigated to rule out an underlying congenital heart disease.     

The use of non-steroidal anti-inflammatory drugs for patent ductus arteriosus closure in preterm infants

Over the last four decades, non-steroidal anti-inflammatory drugs have been widely used to induce closure of the patent ductus arteriosus (PDA) in preterm infants. Evidence to support this practice is lacking, despite performance of >50 randomized trials. The credibility of those trials may have been compromised by high rates of open treatment in controls, era of study prior to advent of modern practices, or inclusion of insufficient numbers of very immature infants. Meta-analyses show little impact of those factors on main conclusions. Essentially all trials reporting important long-term outcomes (other than mortality) initiated treatment within five days after birth, so no evidence regarding later treatment is available. Accruing clinical experience suggests that long-term outcomes are not compromised, and may be improved, with non-interventional management strategies. Future studies to identify preterm infants at greatest risk of potential harm from a persistent PDA, particularly after the second postnatal week, are urgently needed.     

Prophylactic and early targeted treatment of patent ductus arteriosus

Treatment of a haemodynamically significant patent ductus arteriosus (PDA) in the very preterm infant has been an accepted approach for several decades. However, the rationale for closure of PDA has recently been challenged due to reports of success with conservative approaches and the lack of evidence for longer-term benefits from treatment. In this article, we address an approach to assess treatment of those babies most likely to benefit.     

A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus

Ibuprofen (IBU) has previously been shown to be as effective as indomethacin (INDO) in closing the patent ductus arteriosus (PDA) of preterm infants, without severely affecting renal hemodynamics or basal cerebral blood flow. We conducted a meta-analysis of randomized trials to compare the efficacy and safety of IBU and INDO for treatment of PDA. Data from the nine relevant trials ( n =566), showed no significant difference in the efficacy of IBU and INDO in PDA closure ( P =0.70). However, five trials ( n =443) provided serum creatinine concentration data that revealed a significantly lower increase favoring IBU ( P < 0.001), and urine output data that showed a significantly lower decrease favoring IBU ( P < 0.001). In two trials ( n =188) the proportion of infants who required postnatal oxygen therapy at 28 days (defined as chronic lung disease) was significantly higher with IBU (52/94; 55.3%) than with INDO (38/94; 40.4%, P < 0.05). No statistically significant differences were found in mortality, intraventricular hemorrhage, necrotizing enterocolitis, surgical ligation, sepsis, retinopathy of prematurity, periventricular leukomalacia, length of hospital stay, gastrointestinal bleeding, re-opening of PDA, back-up treatment, surfactant therapy, or days on a ventilator. Conclusion:ibuprofen and indomethacin have similar efficacy in patent ductus arteriosus closure, but preterm infants treated with ibuprofen experience lower serum creatinine values, higher urine output, and less undesirable decreased organ blood flow and vasoconstrictive adverse effects.     

早产儿动脉导管开放的处理

动脉导管开放(PDA)是早产儿常见病症,导致早产儿血流动力学不稳定,严重者可危及生命,应积极处理.药物关闭PDA仍是最有效、方便和经济的治疗方法,吲哚美辛一直是内科保守治疗的主要用药,PDA关闭率为46%～89%,但吲哚美辛有效血药浓度安全范围较窄,且可导致肾功能障碍、颅内出血、坏死性小肠结肠炎和肠穿孔等不良反应.近年国外采用布洛芬治疗早产儿PDA,取得较好疗效,关闭率为73.0%～95.5%,且对肾脏、脑及消化道血流动力学影响显著减少.药物治疗无效且严重影响心肺功能者可选择手术治疗.     

Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants

The aim of our study was to evaluate whether the prophylactic use of ibuprofen would reduce the incidence of significant patent ductus arteriosus (PDA) and to confirm the effectiveness of ibuprofen as rescue treatment in closing PDA. Eighty preterm infants with gestational age less than 34 wk with infant respiratory distress syndrome (iRDS) were randomized to receive intravenous ibuprofen lysine (10 mg/kg, followed by 5 mg/kg after 24 and 48 h) either within 24 h of life (group A) or after echocardiographic diagnosis of PDA (group B). To evaluate the severity of RDS in each patient, we calculated the initial and highest values of Oxygenation Index (O.I. = mean airway pressure x FiO2 x 100/PaO2) and Ventilatory Index (V.I. = O.I. x mechanical respiratory rate). Other studied variables were ventilatory support, renal function, biochemical and haematological profiles, frequency of bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP). On the 3rd day of life, 8% (3/40) of patients of group A and 53% of patients (21/40) of group B (p < 0.0001) developed a significant PDA. Between patients of group B who presented PDA at 3 d of life 90% (19/21) had a closure of ductus arteriosus after ibuprofen treatment. Initial and highest values of O.I. and V.I. were similar in both groups A and B. No significant differences between the groups were observed in regard to respiratory support, renal function and frequency of BPD, IVH, NEC and ROP. Ibuprofen was not associated with adverse effects. Conclusion: Prophylactic treatment with ibuprofen reduces PDA occurrence in preterm infants with iRDS at 3 d of life in comparison with rescue treatment, but both modes are effective in closing the ductus without significant adverse effects.     

Furosemide in preterm infants treated with indomethacin for patent ductus arteriosus

Objective: To evaluate the effect of furosemide on renal function and water balance in preterm infants treated with indomethacin (3 × 0.2 mg/kg at 12-h intervals) for symptomatic patent ductus arteriosus.
Patients and Methods: We performed a retrospective multi-centre double cohort study in preterm infants <32 weeks of gestational age. Thirty-two infants treated with furosemide (1 mg/kg i.v.) before each indomethacin dose (furosemide group) were matched with 32 infants with indomethacin treatment alone (control-group). Renal effects (urine output, weight gain, serum creatinine, sodium concentration) were registered.
Results: The study groups were comparable for gestational age, birth weight and day of therapy. Pretreatment differences were observed for urine output, weight and serum sodium. However, no differences were noticed in day-to-day urine output change or weight gain between the groups. A significant increase in serum creatinine concentration (50% vs. control, 18%; p < 0.05) and a concomitant significant decrease in serum sodium (–9 vs. control, –3 mmoL/L; p < 0.05) in the furosemide group was observed 72–96 h after starting therapy.
Conclusion: Furosemide before each indomethacin dose resulted in a significant increase in serum creatinine and hyponatremia, without increasing urine output.     

Intravenous Indomethacin therapy in preterm neonates with patent ductus arteriosus

This study examined the response of the patent ductus arteriosus (PDA) to intravenous Indomethacin using serial two dimensional and Doppler echocardiography and documented the complications associated with therapy. Thirty-six preterm neonates who were oxygen and ventilator dependent were studied when they were aged 3-7 days. The PDA initially closed in 22 (61%) and constricted in seven (19%) of the infants. It was non-responsive in five (14%) and the treatment was stopped because of complications in two (6%). Only three (43%) of seven neonates given a second course had PDA closure. In the 25 instances where there was PDA closure following Indomethacin, re-opening was documented echocardiographically on three (12%) occasions. Overall, Indomethacin therapy was successful in 29 (81%) neonates, PDA ligation was required in four (11%) and three died from unrelated causes. Three (8%) neonates developed major complications: multiple gastric perforations in the first, focal ileal perforation in the second, and necrotizing enterocolitis in the third. Treatment failure, PDA ligation and major complications occurred exclusively in neonates less than 28 weeks gestation. In view of the relatively low efficacy and high major complication rate in these extremely preterm infants, a randomized clinical trial needs to be conducted using two dimensional and Doppler echocardiography to allow accurate assessment of the PDA response to intravenous Indomethacin.     

早产大鼠动脉导管开放模型的建立

目的 利用改良的自然发育法构建早产大鼠动脉导管开放模型.方法 基于自然发育法在构建早产大鼠动脉导管开放模型上的缺陷,本研究对实验技术进行了改进,避免固定方式、脱水处理及切片方式对血管管径的影响.将1 只孕19 d 的Wistar 大鼠行剖宫产,取出8 只新生大鼠,脱臼处死后整体包埋、避免脱水、微距切片、水平切片,苏木精-伊红染色后镜下测量动脉导管、主肺动脉、降主动脉内径.结果 孕19 d 大鼠剖宫产术后8 只新生大鼠动脉导管均开放.各血管内径测量结果显示:降主动脉长径:354±106 μm,短径:182±140 μm;动脉导管短径:155±122 μm,面积:36 847±42 582 μm2;主肺动脉长轴:589±150 μm,短轴:174±170 μm.结论 改良的早产大鼠动脉导管开放模型成功构建.     

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

BACKGROUND: Patent ductus arteriosus (PDA) is commonly found in very low-birthweight (VLBW) infants. The presence of respiratory distress syndrome (RDS) is also associated with increased frequency of significant PDA. Intravenous indomethacin has been used to treat and to prevent PDA in premature infants since 1976. However, concern remains regarding the safety of indomethacin, which affects renal, gastrointestinal and cerebral perfusion. Intravenous ibuprofen has recently been used to treat and to prevent PDA premature infants with PDA without reducing cerebral blood flow or affecting intestinal or renal hemodynamics. The aim of the present study is to compare intravenous ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants. METHODS: A total of 63 preterm infants with RDS who had a birthweight of < or =1500 g and gestational age of < or =32 weeks, were enrolled in the present study. All patients were treated with nasal continuous positive airway pressure with additional oxygen supply in inspired air>30%, or with mechanical ventilation. The patients' serum platelet counts were>100,000/uL, and serum creatinine values were <1.5 mg/dL. There were no 3-4 grade intraventricular hemorrhages before randomization, and all patients were aged 2-7 days and had echo-cardio-graphic evidence of significant PDA. Patients were randomized into two groups: the first group of neonates (group A, n = 32) received intravenous ibuprofen lysine 10 mg/kg, followed by 5 mg/kg after 24 and 48 h; the second group (group B, n = 31) received intravenous indomethacin 0.2 mg/kg every 12 h for three doses. RESULTS: Patent ductus arteriosus closed in 27 patients from the ibuprofen group (84.4%) and in 25 patients from the indomethacin group (80.6%). PDA reopened in three patients from the ibuprofen group (9.4%) and in three patients from the indomethacin group (9.7%). One patient in the ibuprofen group and two patients in the indomethacin group required ductal ligation. Serum creatinine and blood urea nitrogen (BUN) concentrations were lower in the ibuprofen group than in the indomethacin group. Urine output and creatinine clearance values were higher in the ibuprofen group than in the indomethacin group. CONCLUSIONS: Ibuprofen therapy is as efficacious as indomethacin for the treatment of PDA in preterm infants. Infants treated with ibuprofen have higher creatinine clearance and urine output and lower serum creatinine and BUN values than infants treated with indomethacin.     

氨基末端脑钠肽前体预测早产儿症状性动脉导管未闭的价值

目的 探讨氨基末端脑钠肽前体(NT-proBNP)预测早产儿症状性动脉导管未闭(sPDA)的价值。方法 选择2014年6月至2015年4月出生、胎龄≤32周、48 h内超声心动图确定存在动脉导管的早产儿为研究对象,监测其临床表现,于生后3 d及5 d检测血清NT-proBNP水平并行超声心动图检查,根据患儿临床表现、超声心动图结果分为sPDA组及非症状性动脉导管未闭(asPDA)组,分析血清NT-proBNP水平与超声指标的关系,比较两组间相同日龄血清NT-proBNP水平,ROC曲线确定血清NT-proBNP水平预测sPDA的敏感性、特异性。结果 共69例早产儿纳入研究,其中sPDA组13例,asPDA组56例。血清NT-proBNP水平与动脉导管管径、左房内径与主动脉根部内径比值(LA/AO)呈正相关关系(分别r=0.856、0.713,均 PPCI:0.892~1.000,PCI:0.848~1.000,P结论 NT-proBNP可能是动脉导管分流量的量化指标;生后3 d 及5 d血清NT-proBNP水平的检测均有助于早期预测sPDA。     

N-terminal-pro-brain natriuretic peptide: a guide for early targeted indomethacin therapy for patent ductus arteriosus in preterm Infants

Aim: To determine whether N‐terminal‐pro‐brain natriuretic peptide (NT‐proBNP) level could be an effective guide for early targeted indomethacin therapy for patent ductus arteriosus (PDA) in preterm infants. Methods: An interventional study involved preterm infants, born at <33 weeks of gestation, who had plasma NT‐proBNP levels obtained at day 2 of life. Indomethacin therapy was given if plasma NT‐proBNP level was ≥10 180 pg/mL, the cut‐off for predicting hemodynamic significant PDA (hsPDA). Echocardiograms were performed within 6 h at the time of plasma NT‐proBNP collection and again at day 7, or whenever clinical hsPDA was suspected. Primary outcomes were the incidence of later hsPDA and unnecessary exposure rate to indomethacin. Results: Fifty infants were enrolled. On day 2, 19 (38%) infants had plasma NT‐proBNP above the cut‐off and received indomethacin therapy; none of them developed later hsPDA, while 1 of 31 infants with NT‐proBNP below the cut‐off level developed clinical hsPDA. Unnecessary exposure to indomethacin occurred in two infants (11%). Overall, no enrolled infants had either reopening of ductus or PDA ligation. Conclusion: Using NT‐proBNP level on day 2 as a guide for early targeted indomethacin therapy reduced later onset of hsPDA and the number of unnecessary exposures to indomethacin.     

Precordial contrast echocardiographic detection of patent ductus arteriosus in small preterm infants

Summary Clinical detection of patent ductus arterious (PDA) remains an important and challenging problem in the small preterm infant with respiratory distress. In this study, PDA was diagnosed in 28 small preterms using an improved contrast echocardiographic method. In these infants, the injection of saline into the aorta generated echoes which were imaged at the pulmonary valve. This was accomplished using a conventional M-mode ultrasound transducer applied at the usual precordial position. Contrast echo studies were compared with the degree of ductal patency shown by single film aortography. Ductal patency was detected by contrast echo in 29 of 31 instances of aortographically proven PDA. Indirect echo indices commonly used for detection of PDA (cardiac chamber enlargement) may be limited since factors other than left-to-right shunt can cause cardiac enlargement in distressed small preterms. This direct contrast echo technique is an easily performed, sensitive, qualitative method for confirmation of the diagnosis of PDA in small preterm infants. This work was supported in part by grant 5507 RR05551-17 from U.S. Public Health Service, Bethesda, Maryland Presented to members of the Cardiology Section at the 20th Annual Meeting of the Society for Pediatric Research, April 29–May 2, 1980, San Antonio, Texas     

早期口服布洛芬治疗极低出生体重儿动脉导管未闭的临床研究

目的：探讨早期口服布洛芬治疗极低出生体重儿（VLBWI）动脉导管未闭（PDA）的临床效果和安全性。方法：生后24 h内经床边心脏彩超确诊的有临床症状的VLBWI PDA 64例,随机分为治疗组和对照组,每组32例。治疗组生后24 h内口服布洛芬,首剂10 mg/kg,第2、3剂5 mg/kg,每剂间隔24 h。对照组给予安慰剂生理盐水1 mL/kg,第2、3剂0. 5 mL/kg,每剂间隔24 h。观察两组患儿的治疗效果及不良反应。结果：第1疗程结束后治疗组动脉导管关闭率为84%,明显高于对照组的41%,两组比较差异有统计学意义（P＜0.01）。治疗组脑室周围白质软化和支气管肺发育不良的发生率明显低于对照组（P＜0.05）;机械通气时间和平均住院时间明显短于对照组（P＜0.05）。两组脑室内出血、早期肺出血、坏死性小肠结肠炎的发生率等差异无统计学意义（P＞0.05）,且均未发现明显不良反应。结论：早期口服布洛芬治疗VLBWI PDA可以减少部分近期并发症的发生率,缩短住院时间,且未发现明显不良反应。     

早期早产儿动脉导管未闭发生的危险因素的病例对照研究

目的 探讨早期早产儿动脉导管未闭(PDA)发生的危险因素,为进一步减少早产儿PDA 的发生提供临床依据。方法 将2013 年1 月至2014 年12 月住院治疗的136 例诊断为有血流动力学意义的PDA(hs-PDA)的早期早产儿(胎龄≤ 32 周)设为病例组,按1:1 的比例从同期住院的早期早产儿中按匹配病例对照原则抽取136 例无hs-PDA 的早产儿作为对照组,两组匹配因素包括性别及胎龄。收集可能与PDA 发生有关的新生儿基本情况、母亲孕期及围产期情况等资料,应用多因素条件logistic 回归分析筛选PDA 发生的危险因素。结果 单因素分析结果显示:新生儿感染性疾病、新生儿呼吸窘迫综合征(RDS)、生后24 h 内血小板计数减低及低出生体重与hs-PDA 的发生相关(P<0.05)。多因素条件logistic 回归分析显示新生儿感染性疾病(OR=2.368)及生后24 h 内血小板计数减低(OR=0.996)是hs-PDA 发生的独立危险因素。结论 新生儿感染性疾病及生后24 h 内血小板计数减低会增加早期早产儿hs-PDA 的发生风险。     

Pharmacokinetics of intra-arterial indomethacin treatment for patent ductus arteriosus

Summary We present pharmacokinetic data of prolonged, intra-arterial indomethacin treatment (i.e. induction plus maintenance dose) for symptomatic patent ductus arteriosus (sPDA) in 26 ventilated premature infants. sPDA was assessed by two-dimensional and pulsed Doppler echocardiography. Permanent ductal closure occurred in 20 (76%) infants. Plasma levels of indomethacin were 1.18±0.74; 1.8±1.0; 1.51±0.93 and 1.25±0.98 g/ml (mean±SD) at 12, 24, 48 and 72 h after initial dose administration. All except one patient who responded with ductal closure, showed plasma levels above 0.25 g/ml throughout the 3 day treatment period and no case of sPDA reopening was noted. Although target concentrations over time were not defined, the data indicate that the maintenance levels measured were within the therapeutic range. A negative correlation was found for plasma drug levels and postnatal age (r=0.52;P<0.01). Volume of drug distribution was 0.23±0.18l/kg, total clearance 0.1±0.11 ml/min and elimination constant 0.06±0.05h^–1 (mean±SD). The great variation in pharmacokinetic data reflects the heterogeneity of the population studied with respect to extracellular fluid space, cardiovascular status, serum protein and other parameters.     

Management of the patent ductus arteriosus in preterm infants

Management of the patent ductus arteriosus (PDA) is one of the most contentious topics in the care of preterm infants. PDA management can be broadly divided into prophylactic and symptomatic therapy. Prophylaxis with intravenous indomethacin in extremely low birth weight infants may reduce severe intraventricular hemorrhage. Echocardiography should be routinely used to confirm the presence of a PDA before considering symptomatic therapy. A symptomatic PDA can be managed conservatively, using pharmacotherapy or with procedural closure. Ibuprofen should be considered as the pharmacotherapy of choice for a symptomatic PDA. High-dose ibuprofen may be preferable, especially for preterm infants beyond the first 3 to 5 days of age. If pharmacotherapy fails (after two courses) or is contraindicated, procedural closure may be considered for infants with a persistent PDA with significant clinical symptoms in addition to echocardiographic signs of a large PDA shunt volume and pulmonary over-circulation.