The fate of ductus arteriosus in infants at 23–27 weeks of gestation: from spontaneous closure to ibuprofen resistance

Background: Some extremely preterm infants experience spontaneous closure of the ductus arteriosus. On the other side, a high percentage (22–30%) of preterm infants born at the lower gestational age fail to respond to a single course of ibuprofen.
Aim: To assess if there are clinical characteristics effective as predictive factors for spontaneous closure of the ductus arteriosus, development of patent ductus arteriosus (PDA) and ibuprofen-resistant PDA.
Methods: A cohort of inborn infants less than 28 weeks of gestation were prospectively studied. We distinguished infants who had spontaneous closure of ductus arteriosus, who developed PDA and who developed ibuprofen-resistant PDA.
Results: We studied 34 infants. Eight infants (24%) had spontaneous closure of PDA, 17 infants (50%) had a closure of PDA following the first ibuprofen course, while 9 infants (26%) failed to respond to the first ibuprofen course. Infants born at 23–25 weeks of gestation were found to have lower likelihood of PDA spontaneous closure, and higher risk of developing PDA refractory to ibuprofen therapy. Sepsis was found to increase significantly the risk of ibuprofen failure in closing PDA.
Conclusion: An important percentage of extremely preterm infants exhibited spontaneous closure of PDA. Among clinical characteristics lowest gestational ages predict PDA and ibuprofen-resistant PDA, while sepsis predicts only ibuprofen-resistant PDA.     

Oral medications regarding their safety and efficacy in the management of patent ductus arteriosus

Patent ductus arteriosus (PDA) is a common clinical condition in preterm infants which is inversely related to birth weight and gestational age. Cyclooxygenase inhibitors such as indomethacin and ibuprofen which block the prostaglandin conversion from arachidonic acid are the most commonly used drugs for ductal closure. This review focuses on the safety and efficacy oral medications in the management of PDA in preterm infants. Ibuprofen seems to be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects when compared to indomethacin. PDA closure rates are better with oral than with intravenous ibuprofen probably due to the pharmacokinetic of the drug. However, these medications were reported to be associated with several adverse including transient renal failure, gastrointestinal bleeding and perforation, hyperbilirubinemia and platelet dysfunction. Paracetamol seems be an alternative to PDA therapy with lower adverse events and side effects.     

The fate of ductus arteriosus in infants at 23-27 weeks of gestation: from spontaneous closure to ibuprofen resistance

BACKGROUND: Some extremely preterm infants experience spontaneous closure of the ductus arteriosus. On the other side, a high percentage (22-30%) of preterm infants born at the lower gestational age fail to respond to a single course of ibuprofen. AIM: To assess if there are clinical characteristics effective as predictive factors for spontaneous closure of the ductus arteriosus, development of patent ductus arteriosus (PDA) and ibuprofen-resistant PDA. METHODS: A cohort of inborn infants less than 28 weeks of gestation were prospectively studied. We distinguished infants who had spontaneous closure of ductus arteriosus, who developed PDA and who developed ibuprofen-resistant PDA. RESULTS: We studied 34 infants. Eight infants (24%) had spontaneous closure of PDA, 17 infants (50%) had a closure of PDA following the first ibuprofen course, while 9 infants (26%) failed to respond to the first ibuprofen course. Infants born at 23-25 weeks of gestation were found to have lower likelihood of PDA spontaneous closure, and higher risk of developing PDA refractory to ibuprofen therapy. Sepsis was found to increase significantly the risk of ibuprofen failure in closing PDA. CONCLUSION: An important percentage of extremely preterm infants exhibited spontaneous closure of PDA. Among clinical characteristics lowest gestational ages predict PDA and ibuprofen-resistant PDA, while sepsis predicts only ibuprofen-resistant PDA.     

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.     

Patent ductus arteriosus in preterm infants

Patent ductus arteriosus (PDA) is a major morbidity in preterm infants, especially in extremely premature infants less than 28 weeks. The clinical signs and symptoms of PDA in preterm infants are non specific and insensitive for making an early diagnosis of significant ductal shunting. Functional echocardiography is emerging as a new valuable bedside tool for early diagnosis of hemodynamically significant ductus, even though there are no universally accepted criteria for grading the hemodynamic significance. Echocardiography has also been used for early targeted treatment of ductus arteriosus, though the long term benefits of such strategy are debatable. The biomarkers like BNP and N-terminal pro-BNP are currently under research as diagnostic marker of PDA. The primary mode of treatment for PDA is pharmacological closure using cyclo-oxygenase inhibitors with closure rate of 70–80%. Oral ibuprofen is emerging as a better alternative especially in Indian scenario where parenteral preparations of indomethacin are unavailable and side effects are comparatively lesser. Though pharmacological closure of PDA is an established treatment modality, there is still lack of evidence for long term benefits of such therapy as well as there is some evidence for the possible adverse effects like increased ROP and BPD rates, especially if treated prophylactically. Hence, it is prudent to reserve treatment of PDA to infants with clinically significant ductus on the basis of gestation, birth weight, serial echocardiography and clinical status to individualize the decision to treat.     

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］     

布洛芬与吲哚美辛治疗早产儿动脉导管未闭对照研究的Meta分析

目的　进一步认识布洛芬与吲哚美辛治疗早产儿动脉导管未闭 (PDA)的疗效和不良反应的差异。方法　通过数据库检索出符合分析条件的有关吲哚美辛与布洛芬对照治疗早产儿PDA的研究报告 6篇 ,取其研究结果做Meta分析。结果　布洛芬与吲哚美辛治疗PDA的疗效相同 ,但布洛芬组出现少尿显著少于吲哚美辛组 ,其他不良反应无显著差异。结论　布洛芬治疗PDA的疗效与吲哚美辛相同 ,但引起肾脏不良反应少。     

Comparison of Oral Ibuprofen and Intravenous Indomethacin for the Treatment of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants

ObjectiveThere are few published reports concerning the efficacy of oral ibuprofen for the treatment of patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Oral ibuprofen was compared to intravenous indomethacin regarding efficacy and safety in the treatment of PDA in infants weighting less than 1,000 g at birth.MethodThis was a retrospective study in a single center. Data on ELBW infants who had an echocardiographically confirmed PDA were collected. The infants were treated with either intravenous indomethacin or oral ibuprofen. Rate of ductal closure, need for additional treatment, drug-related side effects or complications, and mortality were compared between the two treatment groups.Result26 infants who received indomethacin and 22 infants who received ibuprofen were studied. The overall rate of ductal closure was similar between the two treatments: it occurred in 23 of 26 infants (88.5%) treated with indomethacin, and in 18 of 22 infants (81.8%) treated with ibuprofen (p = 0.40). The rate of surgical ligation (11.5% versus 18.2%; p = 0.40) did not differ significantly between the two treatment groups. No significant difference was found in post-treatment serum creatinine concentrations between the two groups. There were no significant differences regarding additional side effects or complications.ConclusionIn ELBW infants, oral ibuprofen is as efficacious as intravenous indomethacin for the treatment of PDA. There were no differences between the two drugs with respect to safety. Oral ibuprofen could be used as an alternative agent for the treatment of PDA in ELBW infants.     

Patent ductus arteriosus in infants <29 weeks gestation — outcomes and factors affecting closure

Objective  

To determine Patent ductus arteriosus (PDA) closure rates for extremely preterm infants in a tertiary care centre, factors affecting response to indomethacin and outcomes of these infants relative to their PDA status.     

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.     

Comparison of Oral Ibuprofen with Oral Indomethacin for PDA Closure in Indian Preterm Neonates: A Randomized Controlled Trial

Oral ibuprofen is being used as an alternative to indomethacin in medical management of patent ductus arteriosus (PDA), but limited data exist on oral efficacy of these drugs for PDA closure in India. To assess and compare the efficacy of oral ibuprofen and oral indomethacin for PDA closure in preterm Indian neonates, we designed a randomized controlled study on clinically diagnosed and echocardiographically confirmed hemodynamically significant PDA in preterm neonates. Patients were assigned to receive either oral ibuprofen at a dosage of 10, 5, 5 mg/kg every 24 h or three doses of oral indomethacin (0.20–0.25 mg/kg every 24 h) starting on the third day of life or when diagnosed. A second course of ibuprofen/indomethacin was given, if PDA failed to close within 48 h after the first course. Patients were monitored for complications like oliguria, bleeding, necrotizing enterocolitis, intraventricular hemorrhage, oxygen dependency, and gastrointestinal side effects. The baseline characteristics were comparable in both groups. Of the 83 children enrolled, 57.8 % received oral ibuprofen and 42.1 % received oral indomethacin. The overall closure rate of PDA was 60 and 65.7 % in the ibuprofen and indomethacin groups, respectively. Closure rate was significantly higher when the drugs were administered at an early postnatal age (<8 days) (83.3 % [p = 0.02] in the indomethacin group and 75 % [p = 0.03] in the ibuprofen group) in neonates >28 weeks (ibuprofen group 66.7 % [p = 0.02]; indomethacin group 65.5 % [p = 0.04]) and in babies with birth weight >1,000 g (ibuprofen group 62.2 %; indomethacin group 70 % [p = 0.04 in both groups]). Complications were similar in both groups. The efficacy of both drugs was similar. Poor closure in our study could be because of genetic differences in pharmacokinetics of drug metabolism in the Indian population. Regimens with higher doses or increased duration of treatment may increase the frequency of closure. Studies with larger numbers of subjects with evaluation of pharmacokinetic parameters are therefore required.     

早产儿动脉导管未闭发病机制的研究进展

动脉导管未闭(PDA)是早产儿常见并发症,也是影响早产儿存活率和后遗症发生率的主要原因之一.近年研究发现,早产儿PDA的发生除与自身动脉导管的组织发育不成熟、不易发生重塑有关外,还与动脉导管对氧、血管活性物质的反应异常相关;遗传因素也参与早产儿PDA的发病.     

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.     

静脉注射和口服吲哚美辛治疗早产儿动脉导管未闭疗效比较

目的　探讨静脉注射和口服吲哚美辛治疗早产儿动脉导管未闭 (PDA)的疗效。方法　经心脏彩超确诊的有症状PDA早产儿 4 9例 ,按给药剂型及途径分为静注组 (2 1例 )和口服组 (2 8例 )。剂量及给药间隔时间相同。比较两组PDA关闭率和不良反应。结果　两组单纯PDA闭合、并其他疾病PDA闭合均无显著差异。静注组立即闭合率明显高于口服组 (P <0 .0 5 )。两组较快闭合、迟缓闭合和总闭合虽有差别 ,但无统计学意义。静注组胃肠出血、肾功能减低及高胆红素血症与口服组比较均无显著差异。静注组不良反应总人次明显低于口服组 (P <0 .0 5 )。结论　一定剂量范围内静脉注射或口服吲哚美辛治疗早产儿PDA均具一定有效性和安全性 ,但口服给药不良反应相对较多     

Late closure of the ductus arteriosus using indomethacin in the preterm infant

Several studies have shown a lack of effect of indomethacin therapy for the closure of a patent ductus arteriosus (PDA) in premature infants over 14 days of postnatal age. In this report we describe two cases in which a hemodynamically significant PDA was closed with indomethacin in preterm infants over 20 days of age. The response to indomethacin may be more related to postconceptual age than to actual postnatal age. We suggest that intravenous indomethacin therapy should be attempted before surgical ligation is performed in those premature infants under 34 weeks postconceptual age who have a hemodynamically significant patent ductus arteriosus.     

Patent ductus arteriosus: lack of evidence for common treatments

Patent ductus arteriosus (PDA) is a common diagnosis among extremely premature infants, especially in those with lung disease. Treatments are often used to close the PDA. Despite nearly three decades of research, the question of whether the benefits of treatments to prevent ductal patency or promote closure outweigh the risks of these treatments remains unanswered. The authors rarely use treatments designed to close the PDA. This article reviews three considerations in support of this restrained approach: rates of spontaneous closure of the ductus arteriosus; adverse effect of persistent ductal patency; and benefits and risks of treatments for closure.     

Paracetamol Therapy for Patent Ductus Arteriosus in Premature İnfants: A Chance Before Surgical Ligation

Patent ductus arteriosus (PDA) remains a common problem in premature infants. Treatment options include pharmacologic therapy and surgical ligation, but these are associated with potentially significant adverse effects. This report describes the effect of administering oral paracetamol to premature neonates with PDA. The study enrolled seven premature neonates followed up with the diagnosis of hemodynamically significant PDA (hsPDA) between February and December 2012 and treated with oral paracetamol. Patients with hsPDA were given at least two or more courses of ibuprofen treatment. If this therapy failed to promote ductal closure, the patients with clinical symptoms who had hsPDA defined by echocardiography were treated with oral paracetamol (15 mg/kg every 6 h). If these patients did not respond to paracetamol therapy, the PDA was closed by surgical ligation. The mean gestational age of the seven patients in this study was 26.1 weeks, and their mean birth weight was 936 g. Paracetamol treatment was started at 36.2 ± 11.6 days. The mean internal ductal diameter was 2.0 ± 0.2 mm, and the left atrium-to-aorta ratio was 1.5 ± 0.2. All the patients were administered oral paracetamol because of no response to ibuprofen treatment. The hsPDA was successfully closed with oral paracetamol in five (71.4 %) of the seven patients. The remaining two patients had surgical ligation performed, but one of them died. No side effects related to paracetamol were observed. Oral paracetamol may be used as an alternative drug for the management of hsPDA in premature neonates when ibuprofen treatment is unsuccessful and the only other therapeutic option is surgery.     

近红外光谱技术对有血流动力学意义的动脉导管未闭早产儿肠道组织氧饱和度监测价值的前瞻性研究

目的 使用近红外光谱技术研究有血流动力学意义的动脉导管未闭（hemodynamically significant patent ductus arteriosus,hsPDA）早产儿肠道组织氧饱和度（regional oxygen saturation,rSO₂）的变化及规律,初步探索hsPDA早产儿肠道组织血氧水平变化的临床意义。 方法 前瞻性选取2017年10月至2020年10月深圳市龙岗中心医院新生儿科收治的胎龄<32周和/或出生体重<1 500 g的动脉导管未闭（patent ductus arteriosus,PDA）早产儿。按照hsPDA的诊断标准分为hsPDA组和无血流动力学意义的动脉导管未闭（non-hemodynamically significant patent ductus arteriosus,nhsPDA）组,将hsPDA组早产儿根据口服布洛芬后动脉导管关闭情况分为hsPDA关闭亚组和hsPDA未闭亚组。分别在诊断PDA时及治疗后测定血流动力学指标,持续监测患儿肠道组织rSO₂水平,分析其变化规律。 结果 共有241例PDA早产儿纳入研究,其中hsPDA组55例（22.8%）,nhsPDA组186例（77.2%）;hsPDA关闭亚组36例（65%）,hsPDA未闭亚组19例（35%）。hsPDA组左心房内径/主动脉根部内径值大于nhsPDA组,左室射血分数和短轴缩短率均低于nhsPDA组（P<0.05）。hsPDA组患儿肠道组织rSO₂在诊断后6 h内各时间点（1、2、4、6 h）均低于nhsPDA组（P<0.05）;hsPDA组早产儿肠道组织rSO₂随时间呈下降趋势（P<0.05）,至6 h时达最低值（0.448±0.014）。hsPDA关闭亚组左心房内径/主动脉根部内径值低于hsPDA未闭亚组,左室射血分数和短轴缩短率高于hsPDA未闭亚组（P<0.05）。hsPDA关闭亚组患儿肠道组织rSO₂在治疗后48~96 h内各时间点（48、72、96 h）均高于hsPDA未闭亚组（P<0.05）;hsPDA关闭亚组早产儿肠道组织rSO₂从治疗24 h后随时间呈上升趋势（P<0.05）,至96 h达最高值（0.578±0.031）。 结论 hsPDA对早产儿肠道组织氧合有影响,可通过近红外光谱技术持续监测hsPDA早产儿肠道组织rSO₂变化趋势指导临床管理。     

Treatment of patent ductus arteriosus with ibuprofen

AIM—To evaluate the efficiency and side effects of ibuprofen for the early treatment of patent ductus arteriosus (PDA)and compare it with indomethacin.METHODS—Forty preterm infants with gestational ages of less than 33 weeks, with respiratory distress syndrome (RDS) and echocardiographically confirmed PDA, were randomly assigned at days 2 to 3 of life to receive either intravenous indomethacin 3 × 0.2 mg/kg at 12 hour intervals or intravenous ibuprofen 1 × 10 mg/kg, followed by 5 mg/kg 24 and 48 hours later.RESULTS—PDA closed in 15 of 20 patients from the indomethacin group (75%) and in 16 of 20 (80%) from the ibuprofen group. Seven patients (three indomethacin, four ibuprofen) required a second treatment with indomethacin and in five (three in the indomethacin group and two in the ibuprofen group) the duct was ultimately ligated. Ibuprofen patients had a better urinary output and showed no increase in serum creatinine concentrations compared with the indomethacin group. Ibuprofen was not associated with any other side effect.CONCLUSIONS—Ibuprofen treatment seems to be as efficient as indomethacin in closing PDA on the third day of life in preterm infants with respiratory distress syndrome and seems to have fewer renal side effects.     

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.