Atrial natriuretic peptide in the diagnosis of patent ductus arteriosus

The aim of this study was to measure plasma atrial natriuretic peptide in preterm infants with a patent ductus arteriosus before and after closure with indomethacin. Atrial natriuretic peptide was measured in 28 preterm infants with clinical and echocardiographic evidence of a patent ductus arteriosus and in eight preterm infants who did not develop clinical evidence of a patent ductus arteriosus. Plasma concentration of atrial natriuretic peptide was measured by radioimmunoassay. In 18 infants the patent ductus arteriosus closed after one course of indomethacin; atrial natriuretic peptide levels decreased from median 1240 pg/ml (range 201-5483 pg/ml) to 266 pg/ml (range 62-1108 pg/ml). In four infants the patent ductus arteriosus closed after two courses of indomethacin and two infants had surgical ligation after indomethacin treatment failed. The patent ductus arteriosus closed spontaneously in four infants (atrial natriuretic peptide median level 152 pg/ml, range 61-495 pg/ml). In the eight infants without patent ductus arteriosus, atrial natriuretic peptide level was median 224 pg/ml (range 38-876 pg/ml). Measurement of plasma atrial natriuretic peptide concentration has a role in predicting when indomethacin treatment is indicated.     

Indomethacin and cerebral blood flow in premature infants treated for patent ductus arteriosus

Central blood flow (CBF) was estimated by an intravenous 133-xenon technique in six preterm infants before and after administration of indomethacin for closure of patent ductus arteriosus. CBF fell in all infants (range 12%–40%), the mean fall was 24% (P<0.005). Though none of the infants showed signs of impaired cerebral function during or following the injections, the results do not indicate whether or not the use of indomethacin is a potential hazard.Abbreviations PDA patent ductus arteriosus - CBF cerebral blood flow - PaCO₂ arterial carbon dioxide tension - MAP mean arterial blood pressure     

Plasma levels of natriuretic peptides and hemodynamic assessment of patent ductus arteriosus in preterm infants

The main purpose of this study was to investigate whether circulating natriuretic peptides in premature infants reflect the hemodynamic significance of a patent ductus arteriosus (PDA). The study comprises 120 examinations in 55 premature infants with a mean gestational age of 27.2 wk and a mean birthweight of 933 g. Based on clinical and echocardiographic findings, the hemodynamic influence of ductal shunting was classified as small, moderate or large. Blood samples for N-terminal proatrial natriuretic peptide (Nt-proANP) and brain natriuretic peptide (BNP) were analysed after completion of the clinical part of the study. Linear regression indicated a very strong association between Nt-proANP and BNP (adjusted R = 0.89). The mean levels of Nt-proANP and BNP increased with the size of the shunt through a PDA, and peptide values followed hemodynamic alterations. The size of PDA accounted for 50% and 47% of the total variation in the plasma values of Nt-proANP and BNP, respectively. In detecting an echocardiographically significant PDA, the area under a ROC curve was 0.94 for Nt-proANP and 0.90 for BNP. Conclusion: The magnitude of shunting through a PDA is the main determinant of plasma levels of natriuretic peptides in premature infants. Nt-proANP and BNP seem to have the same pattern of secretion. Our findings indicate that measurements of natriuretic peptides may provide clinically relevant information in the hemodynamic assessment of premature infants.     

Early N-terminal pro-brain natriuretic peptide measurements predict clinically significant ductus arteriosus in preterm infants

We report a blinded, prospective study of the diagnostic utility of N-terminal pro-brain natriuretic peptide (NTproBNP) measurements for predicting clinically significant patent ductus arteriosus (PDA) and assessing closure.
Methods:  Plasma NTproBNP was measured during the first week in 100 preterm babies (mean gestation 28.8 ± 2.9 weeks; mean birth weight 1224 ± 512 g). Echocardiography was performed between days 5 and 7 by operators, blinded to NTproBNP concentration.
Results: NTproBNP peaked on days 2 and 3, declined by day 7. Twenty babies, later treated for PDA, had significantly higher NTproBNP levels throughout. Areas under receiver operating characteristic (ROC) curves were 0.896, 0.897 and 0.931 on days 2, 3 and 7, respectively (p < 0.0001). A concentration > 2850 pmol/L had diagnostic sensitivity of 90% and specificity of 89% (95% CI: 68, 99; likelihood ratio 8.10). Ductal closure was associated with a fall in mean NTproBNP from 3003 to 839 pmol/L (p < 0.001).
Conclusion:  N-terminal pro B-type brain natriuretic peptide (NTproBNP) concentrations peaked and then declined in the first week but remained higher in preterm babies whose PDA required treatment. NTproBNP on day 3 predicted whether a neonatal physician blinded to results would treat a PDA. Fall in plasma NTproBNP indicated closure.     

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.     

Echocardiographic assessment of patent ductus arteriosus shunt flow pattern in premature infants

AIMS—To identify the patent ductus arteriosus (PDA) shunt flow pattern using Doppler echocardiography; and to assess whether it could be used to predict the development of clinically significant PDA.
METHODS—Premature infants weighing under 1500 g, who required mechanical ventilation, and in whom daily echocardiography could be performed from day 1 until the ductus closed, and on day 7 to confirm closure, were studied. The PDA shunt flow was identified from four Doppler patterns, and the closed pattern of a closed duct was also presented. Clinically significant PDA was diagnosed when there was colour Doppler echocardiographic evidence of left to right ductal shunt associated with at least two of the following clinical signs: heart murmur (systolic or continuous); persistent tachycardia (heart rate>160/min); hyperactive precordial pulsation; bounding pulses; and radiographic evidence of cardiomegaly or pulmonary congestion.
RESULTS—Of 68 infants enrolled into this study, clincally significant PDA developed in 31. The most recordable sequence of transition change of shunt flow pattern for clinically significant PDA was: pulmonary hypertension pattern, to growing pattern, to pulsatile pattern, to closing pattern, to closed pattern. And that for non-clinically significant PDA was: pulmonary hypertension pattern, to closing pattern, to closed pattern. The growing and the pulsatile patterns were mostly documented in infants with clinically significant PDA. The first documented growing pattern to predict clinically significant PDA gave a sensitivity of 64.5% and a specificity of 81.1%; the first documented pulsatile pattern gave a sensitivity of 93.5% and a specificity of 100%.
CONCLUSION—Doppler echocardiographic assessment of PDA shunt flow pattern during the first 4 days of life is useful for predicting the development of clinically significant PDA in premature infants. At that stage, the closing or closed Doppler pattern indicates that infants are not at risk of developing clinically significant PDA; the growing or pulsatile Doppler pattern indicates a continuing risk of developing clinically significant PDA.

     

血N端脑钠肽前体在早产儿症状性动脉导管未闭诊治中的应用价值

目的探讨血浆N端脑钠肽前体(NT-pro BNP)在早产儿症状性动脉导管未闭(s PDA)诊治中的临床应用价值。方法选取2013年10月—2014年9月入住新生儿重症监护病房、胎龄28~32周、出生体质量??1 500 g的早产儿107例,分别于生后第4、7天检测NT-pro BNP,采血后30 min内行超声心动图检查。根据生后第4天超声心动图检查结果分PDA组(39例)与对照组(68例);PDA组根据有无超声血流动力学显著改变及临床表现分为症状性PDA(s PDA组,20例)和无症状性PDA(as PDA组,19例);s PDA组再根据是否服用布洛芬分为治疗组(13例)与非治疗组(7例)。结果生后第4天,s PDA组患儿血浆NT-pro BNP水平高于as PDA组,as PDA组高于对照组,差异均有统计学意义(P??0.05);生后第7天,s PDA组患儿血浆NT-pro BNP水平高于as PDA组和对照组,差异有统计学意义(P??0.05),as PDA组与对照组的差异则无统计学意义(P??0.05)。治疗组生后第7天血浆NT-pro BNP水平较第4天显著下降,差异有统计学意义(P??0.05);非治疗组生后第7天与第4天血浆NT-pro BNP水平的差异无统计学意义(P??0.05)。PDA患儿生后第4天血浆NT-pro BNP水平与动脉导管(DA)直径、左心房/主动脉根部内径比值(LA/AO)及DA直径与左肺动脉内径比值(TDD/LPA)呈正相关(r=0.498~0.670,P均??0.05)。生后第4天血浆NT-pro BNP水平预测s PDA的ROC曲线下面积(AUC)为0.969(95%CI:0.938~1.000),NT-pro BNP水平在13 964 pg/m L时,诊断s PDA的灵敏度为95%,特异度为95.4%。结论 s PDA早产儿血浆NT-pro BNP水平明显增高,治疗后下降。第4天血浆NT-pro BNP是预测s PDA的敏感指标,动态监测血浆NT-pro BNP水平变化对指导早产儿PDA治疗策略的选择有重要临床价值。     

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.     

Clinical and echocardiographic diagnosis of patent ductus arteriosus in premature neonates

The ductus arteriosus frequently fails to close in premature neonates. Considerable difference in opinion exists around what signifies a hemodynamically significant patent ductus arteriosus (PDA) and how reliable clinical signs are in determining the degree of the left-to-right shunting. Although reliance on clinical signs alone could delay the diagnosis of a PDA, there is insufficient evidence to suggest that early treatment improves outcome. Echocardiography is often used as the gold standard for diagnosing a PDA. A combination of echocardiographic measurements may assist in the early diagnosis of a PDA with a hemodynamically significant degree of left-to-right shunting, especially in extremely premature babies, where closure can be significantly delayed. Decision to treat PDA should be based on a combination of clinical signs and echocardiographic parameters. Monitoring B-type natriuretic peptide may be useful in the diagnosing neonates with symptomatic PDA.     

Pulmonary effects of closure of patent ductus arteriosus in premature infants with severe respiratory distress syndrome

The pulmonary effects of closure of a patent ductus arteriosus (PDA) were investigated in 11 premature infants with severe respiratory distress syndrome. Successful closure of a PDA did not improve the short-term severity of pulmonary disease (24 and 48 h after treatment) as judged by the arterial/alveolar oxygen tension ratio or the amount of ventilatory support. Also, pulmonary mechanics measured 24 h before, 24 and 48 h after treatment, were not statistically different.Conclusion Infants with severe respiratory disease requiring high ventilation pressure and high oxygen concentration, where structural changes in the lungs are already established, will rarely show short-term improvement in pulmonary disease as a result of closure of a PDA. The overall clinical condition may, however, improve as a result of reduced cardiovascular strain. Earlier treatment of a PDA could reduce the ventilation period and the possible risk of developing chronic lung disease.     

Retrolental fibroplasia in premature infants with patent ductus arteriosus treated with indomethacin

Sixteen premature infants were treated with indomethacin, either orally or intravenously, in order to close a symptomatic patent ductus arteriosus requiring mechanical ventilation. Positive effect was obtained in 4 of the 10 orally treated patients and in 1 of the 6 with intravenous administration. Immediate side effects were impairment of renal function, abdominal distension, and restlessness.Although the oxygen administration was guided using a transcutaneous oxymonitor, three severe cases of retrolental fibroplasia occurred. As indomethacin is a nonselective inhibitor of all prostaglandins, it might also cause a constriction of the retinal arteries, and as such be a factor in the development of retrolental fibroplasia in small premature infants.     

High efficacy and minor renal effects of indomethacin treatment during individualized fluid intake in premature infants with patent ductus arteriosus

AIM: To determine the efficacy and the renal side effects of indomethacin treatment for closure of a patent ductus arteriosus (PDA) in premature infants during an individualized fluid regime that avoids hypovolaemia and subsequent prostaglandin-dependent renal perfusion. METHODS: Observational retrospective analysis of the efficacy of indomethacin in premature infants with PDA treated in a single institution from June 1992 to May 2000. The clinical course and renal effects were analysed in the subgroup of infants born from June 1995 to May 2000. The management of infants at risk and the treatment of infants with PDA followed a standardized protocol that included echocardiographic screening for PDA, indomethacin treatment before congestive failure develops (early symptomatic treatment) and an individualized fluid intake. RESULTS: In total, 412 infants with a gestational age < or = 32 wk were identified. Fifty-six infants with a PDA (14%) were treated with indomethacin [mean birthweight 936 (95% confidence interval 866-1006) g; gestational age 27.3 (26.8-27.9) wk]. Indomethacin treatment was successful in 52 infants (93%). The clinical course and renal effects were analysed in 41 infants. Most infants received three indomethacin doses of 0.2 mg kg(-1) every 12 h. Urine output transiently decreased from 5.6 (4.6-6.4) to 4.6 (3.9-5.3) ml kg(-1) (h(-1). Serum creatinine temporarily increased from 0.90 (0.83-0.98) to 1.06 (0.87-1.24)mg dl(-1). Fluid intake was 158 (148-168) ml kg(-1) d(-1) before indomethacin and decreased to 142 (131-154) ml kg(-1) d(-1). CONCLUSION: Indomethacin is very effective for closure of a PDA, even in very premature infants, and is not associated with clinically significant renal side effects.     

Prolonged low-dose indomethacin therapy for patent ductus arteriosus in very low birthweight infants

To determine the efficacy and side-effects of prolonged low-dose indomethacin therapy in very low birthweight (VLBW; <1500 g) infants with a haemodynamically significant patent ductus arteriosus (hsPDA).

Methodology:

Very low birthweight infants admitted over a 16 month period were studied (6 months, retrospectively and 10 months, prospectively). Cross-sectional and M-Mode echocardiograms with pulsed-wave and colour Doppler were performed to assess the significance of ductal patency.

Results:

Forty-one (28%) of 148 VLBW infants were diagnosed to have hsPDA. Indomethacin therapy was successful in 90% after the first course, increasing to 95% after the second course. The recurrence rate after the first course was 3%. Minor and transient complications included oliguria, urea retention, hyponatraemia and thrombocytopenia. Although three infants had focal bowel perforation and the fourth had bowel perforation associated with necrotizing enterocolitis, the incidence of gastrointenstinal pathology was not significantly different from infants without hsPDA and not given indomethacin.

Conclusions:

Very low birthweight infants with hsPDA have a high response rate and low recurrence rate to prolonged lowdose indomethacin therapy. Side-effects were mild and transient. However, it is prudent to be cautious when administering indomethacin in critically ill infants <1000 g with hsPDA who manifest clinical features of bowel ischaemia.     

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］     

Clinical aspects of very‐low‐birthweight infants showing reopening of ductus arteriosus

Background: Indomethacin is used to treat the hemodynamically significant patent ductus arteriosus in premature infants. Some infants show ductus arteriosus reopening after effective constriction by the drug. The purpose of this study was to examine the clinical characteristics of such infants. Methods: We studied 57 very‐low‐birthweight infants with effective constriction of patent ductus arteriosus by the initial course of indomethacin. They were classified into the reopened group if they developed hemodynamically significant patent ductus arteriosus again or into the closed group if they showed complete closure. Clinical characteristics were compared between the two groups. Results: Ductus arteriosus reopening was shown in 15 (26%) of the 57 infants. These 15 infants had successful clinical ductal closure after a subsequent course of indomethacin or oral mefenamic acid treatment or surgical ligation without any severe complications. Infants in the reopened group showed significantly higher rates of developing chronic lung disease at 36 weeks of gestation than those in the closed group (53% vs 18%; P= 0.009). Furthermore, multivariate logistic regression analysis revealed ductus arteriosus reopening was the only independent risk factor for developing chronic lung disease at 36 postconceptional weeks in this population (adjusted odds ratio, 6.1; 95% confidence interval, 1.4–31.2; P= 0.02). Conclusions: Incomplete closure of the ductus arteriosus is associated with recurrence of a clinically significant patent ductus arteriosus and reopening of the ductus after initial closure with indomethacin is associated with chronic lung disease.