Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus.

Survival of extremely premature infants (< 27 weeks' gestational age) has improved over the past two decades. Indomethacin prophylaxis was used in these infants, who have the highest mortality and morbidity rates, to reduce the incidence of intraventricular hemorrhage and patent ductus arteriosus (PDA). Medical records of 65 extremely premature infants born at our institution between 1995 and 2001 were reviewed retrospectively to determine whether treatment of PDA with indomethacin in the first 48 hours of life reduces the need for PDA ligation or increases neonatal morbidity, when compared to treatment begun later. Thirty infants in the early treatment group (ETG) were treated during the first 48 hours after birth, and 32 infants in the standard treatment group (STG) were managed expectantly for PDA. Three infants died in the first hours of life and were eliminated from further analysis. ETG infants were 24.9 +/- 1.1 (mean +/- SD) weeks' gestation with a birth weight of 678 +/- 143 g. STG infants were 25.3 +/- 1.1 weeks (NS) and 730 +/- 125 g (NS). Hemodynamically significant PDA was diagnosed or confirmed by echocardiography in 19 ETG patients and 17 STG patients. Of the patients with hemodynamically significant PDA, 1 (5%) ETG patient and 6 (35%) STG patients underwent surgical ligation (p = 0.033). Necrotizing enterocolitis (NEC) with intestinal perforation was the most serious morbidity and occurred in 20% of infants in the ETG, but in no STG infant (p = 0.011). Four of the six infants in the ETG with NEC and intestinal perforation died. The overall mortality rate for all infants studied was 28%. We conclude that in extremely premature infants, use of indomethacin during the first 48 hours of life was associated with a reduced need for PDA ligation, but an increased risk of NEC with intestinal perforation.     

Genetics of patent ductus arteriosus susceptibility and treatment

The ductus arteriosus is a vital fetal structure designed to close shortly after birth. Although many physiologic and pharmacologic investigations have characterized the closure of this structure, genetic studies of persistent patency of the ductus arteriosus (patent ductus arteriosus, PDA) are relatively recent. Progress in the identification of specific genes associated with PDA is well behind that of many adult-onset diseases because of several reasons ranging from the lack of large biorepositories for this unique population to the belief that any genetic contribution to PDA is minimal. Viewing the PDA as a complex, developmentally influenced disease with both genetic and environmental risk factors has resulted in initial successes in some genetic studies. We will introduce several genetic approaches, which have been or are currently being applied to the study of PDA, that have been successful in identifying polymorphisms associated with adult diseases. Genetic investigations of PDA will be discussed with respect to heritability, in general, and to specific risk genes. Several animal models that have been used to study PDA-related genes will also be presented. Further advances in discovering genetic variation causing PDA will drive the more rational use of current therapies, and may help identify currently unknown targets for future therapeutic manipulation.     

Low-dose continuous indomethacin in early days of age reduce the incidence of symptomatic patent ductus arteriosus without adverse effects

We conducted a comparative study to evaluate whether the low-dose continuous indomethacin therapy in the early days of age would reduce incidence of the symptomatic patent ductus arteriosus (PDA) without the adverse effects. Thirty-seven infants were in the historical comparison group, and 39 infants were given low-dose indomethacin continuously (0.004 mg/kg/h) from 6-12 postnatal hours until the recognition of closing PDA. Low-dose continuous indomethacin significantly decreased the incidence of symptomatic PDA at 5 days of age (p < 0.01) as compared with the historical comparison group. There was no episode of decreasing urinary output and necrotizing enterocolitis in the indomethacin group. We conclude that the low-dose continuous indomethacin therapy results in decreasing the incidence of symptomatic PDA without significant adverse reactions.     

口服布洛芬和吲哚美辛治疗早产儿动脉导管未闭的效果及其影响因素

目的 比较口服布洛芬和吲哚美辛治疗早产儿动脉导管未闭(patent ductus arteriosus,PDA)的效果和安全性,并分析影响吲哚美辛治疗效果的因素. 方法 采用回顾性对照研究,2007年1月1日至2009年12月30日纳入的有临床症状的PDA早产儿160例为吲哚美辛组,2009年12月31日至2011年1月31日纳入的44例早产儿为布洛芬组.吲哚美辛组鼻饲吲哚美辛(25 mg/片),每次0.2 mg/kg,第2剂与第1剂间隔12h,第3剂与第2剂间隔24 h,3剂为1个疗程;布洛芬组口服布洛芬悬液(40 g/L),首剂10 mg/kg,第2、3剂均为5 mg/kg,每剂间隔24 h,3剂为1个疗程.采用卡方、两独立样本t检验和秩和检验比较2组导管的关闭情况及不良反应,用Logistic 回归模型分析影响吲哚美辛治疗效果的因素. 结果 (1)治疗效果比较:布洛芬组1个疗程动脉导管关闭率、2个疗程动脉导管关闭率和总关闭率分别为68.2％(30/44)、9.1％(4/44)和77.3％(34/44),与吲哚美辛组[63.8％(102/160)、6.9％(11/160)和70.6％ (113/160)]差异无统计学意义(x2分别为0.297、0.030和0.757,P均＞0.05).(2)不良反应:吲哚美辛组尿量＜1 ml/(kg?h)和血肌酐＞88μmol/L的发生率分别为21.3％(34/160)和26.9％(43/160),均高于布洛芬组[6.8％(3/44)和9.1％(4/44)],差异有统计学意义(x2分别为4.841和6.156,P均＜0.05).(3)影响吲哚美辛疗效的因素:胎龄小(OR=2.563,95％CI:1.099～5.976,P=0.029)、合并败血症(OR=4.575,95％CI:1.782～26.768,P=0.009)和新生儿呼吸窘迫综合征(OR=2.407,95％CI:1.023～5.664,P=0.044)是影响早产儿吲哚美辛治疗PDA疗效的危险因素,而母亲产前使用地塞米松(OR=0.530,95 ％CI:0.312～0.901,P=0.018)是保护因素. 结论 口服布洛芬与吲哚美辛治疗早产儿PDA疗效相当,但布洛芬对肾功能的影响较小,一些因素如败血症等影响吲哚美辛的疗效.     

Ductal closure with intravenous paracetamol: a new approach to patent ductus arteriosus treatment

Objectives: Indomethacin and ibuprofen are commonly used in the treatment of hemodynamically significant patent ductus arteriosus (hsPDA). These drugs are associated with serious adverse events, including gastrointestinal perforation, renal failure and bleeding. The role of paracetamol has been proposed for the treatment of PDA.

Methods: We report a series of 11 neonates (birth weight: 415–1580?g; gestational age: 23–30.3 weeks) who were treated with paracetamol for a hsPDA. Neonates with hsPDA were treated with paracetamol in the presence of contraindications to ibuprofen or indomethacin. The condition of significant PDA was defined by the presence of at least one of the following criteria: internal ductal diameter # 1.4?mm/kg body weight, left atrium (LA)-to-aortic (Ao) root ratio >?1.4, unrestrictive pulsatile transductal flow, reverse or absent diastolic flow in the descending aorta along with clinical findings. Intravenous (IV) paracetamol was given at doses 15?mg/kg every 6?h for three days.

Results: Successful ductal closure was achieved in 10 out of 11 babies (90.9%). No adverse or side effects were observed during the treatment.

Conclusions: On the basis of these results, paracetamol could be considered as a promising and safe therapy for the treatment of PDA in preterm infants.     

Necrotizing enterocolitis and gastrointestinal complications after indomethacin therapy and surgical ligation in premature infants with patent ductus arteriosus.

BACKGROUND: Indomethacin is the most frequently used pharmacological agent for closure of a patent ductus arteriosus (PDA) in premature infants. However, reports of complications, particularly, necrotizing enterocolitis (NEC) and isolated gastrointestinal perforation have generated concerns about the use of this medication. OBJECTIVES: A retrospective study to compare the incidence of NEC, NEC-related gastrointestinal complications and isolated gastrointestinal perforation among premature infants treated for a PDA with either, indomethacin alone (I), surgical ligation alone (L), or indomethacin followed by surgical ligation (I-L). METHODS: The medical records of 224 infants that underwent treatment, either pharmacological or surgical, for a PDA, confirmed by echocardiography, over a 4-year period (1995 to 1998) were analyzed. Treatment history and gastrointestinal complications were reviewed. RESULTS: Of the 224 infants, 108 (48.2%) were treated with I, 50 (22.3%) by L, 66 (29.5%) with I-L. The clinical characteristics of the three treatment groups were similar and no differences in the incidence of NEC were observed between groups. NEC occurred in 14 (13%) of the I group, seven (14%) of the L group, and eight (12%) of the I-L group. The rate of NEC related gastrointestinal complications and isolated gastrointestinal perforation were also similar among groups. CONCLUSION: In this large retrospective study, indomethacin treatment for a significant PDA in premature infants was not associated with a greater risk for NEC or NEC-related gastrointestinal complications than surgical ligation.     

Renal impairment associated with indomethacin treatment for patent ductus arteriosus in extremely preterm neonates--is postnatal age at start of treatment important?

OBJECTIVE: To study serum creatinine (SCr) levels following indomethacin for patent ductus arteriosus (PDA) closure in extremely preterm neonates in relation to postnatal age at the start of treatment. METHODS: This was a retrospective (January 2000-December 2002) analysis of data on preterm neonates (gestation <29 weeks) who received indomethacin for PDA. Pre-existing renal malformation and/or impairment and high serum levels of nephrotoxic drugs were criteria for exclusion. RESULTS: Indomethacin was commenced at postnatal age <7 days and >or=7 days in 60 (group 1) and 30 (group 2) neonates, respectively. The median (Q1, Q3) gestational age and birth weight for group 1 and group 2 neonates were 25 (23, 27) vs. 25 (24, 26) weeks and 740 (620, 909) vs. 780 (663, 966) grams, respectively. Postnatal age <7 days at start of indomethacin was associated with higher baseline (0.083 (0.074, 0.090) vs. 0.073 (0.054, 0.083) mmol/L, p=0.001) and peak SCr levels (0.099 (0.089,0.109) vs. 0.090 (0.064, 0.104) mmol/L, p=0.015). Logistic regression analysis controlling for gestational age and baseline SCr level indicated that postnatal age >or=7 days was a risk factor for elevated SCr after indomethacin (OR=13.4, 95% CI: 3.8-46.6, p < 0.001). CONCLUSION: Postnatal age >or=7 days at the start of indomethacin is a predictor of a significant rise in SCr in extremely preterm neonates.     

Correlation analysis between echocardiographic flow pattern and N-terminal-pro-brain natriuretic peptide for early targeted treatment of patent ductus arteriosus

Abstract

Objective: Echocardiographic flow patterns of patent ductus arteriosus (PDA) are useful to predict the development of hemodynamically significant ductus in premature infants. N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations seem to be useful to detect PDA. We investigated how NT-proBNP levels change on the basis of different flow patterns during the first day of life, and whether NT-proBNP might represent a reliable decision tool in PDA management.

Methods: Neonates with gestational age <32 weeks were assessed prospectively, using paired Doppler-echocardiographic evaluation and NT-proBNP values, at T0 (6–24?h of life), and daily until ductal closure.

Results: At T0, NT-proBNP concentrations of 41 neonates correlated to the kind of pattern (p?=?0.018) with the highest values in neonates with pulsatile or growing patterns. A value <9854?pg/ml identified neonates with spontaneous closure (sensitivity 71.8%, specificity 100%). Overall, 32 infants needed treatment. Pre-treatment NT-proBNP values increased compared to those at T0, significantly in neonates with growing pattern at T0 (p?=?0.001). After treatment, NT-proBNP concentrations decreased compared to pre-treatment values (p?=?0.0024), more markedly in the responders than in the non-responders (p?=?0.042).

Conclusions: NT-proBNP concentrations at T0 show a good agreement with different flow patterns and represent a useful tool to identify neonates at risk of developing hemodynamically significant PDA.     

Treatment strategies to prevent or close a patent ductus arteriosus in preterm infants and outcomes.

OBJECTIVE: To describe the current use of treatments to prevent or treat patent ductus arteriosus (PDA) in preterm infants, examine the association between different treatment strategies and neonatal outcomes and review the variation in these practices between centers. STUDY DESIGN: Cohort study of infants born between 23 and 30 weeks gestation managed by the Pediatrix Medical Group from 1997 to 2004. We collected data on demographics, indomethacin and ligation, and outcomes of the following five groups: prophylactic indomethacin treatment: infants treated with indomethacin on day of life (DOL) 0 or 1; indicated indomethacin treatment: infants treated with indomethacin after DOL 1; PDA without treatment: infants with a PDA without report of treatment; ligation only: infants with a PDA ligation without use of indomethacin and no PDA: infants without a PDA and without treatment. RESULTS: There were 6189 (18%) patients who received prophylactic indomethacin, 5690 (16%) patients received indicated treatment, 3886 (11%) patients had a PDA without treatment, 702 (2%) patients received ligation only and 18 136 (52%) patients had no PDA. In multivariate analysis, mortality among survivors to 2 days of age was lower (odds ratio (OR) 0.6, 95% confidence interval (CI) 0.5 to 0.7, P<0.01) and chronic lung disease, isolated intestinal perforation and severe retinopathy of prematurity (stages 3 and 4) were higher (OR 1.5, 95% CI 1.3 to 1.6, P<0.01; OR 1.5, 95% CI 1.1 to 2.0, P<0.01 and 1.4, 95% CI 1.2 to 1.6, P<0.01, respectively) in the indicated treatment group compared with the PDA without treatment group. The proportion of infants receiving prophylactic indomethacin among all infants and infants receiving indicated treatment among neonates with a report of a PDA varied by site from 0 to 59% (median 9.5%) and 0 to 100% (median 62%), respectively. CONCLUSIONS: Indomethacin use for intraventricular hemorrhage prevention and/or treatment of a PDA is common, but the selection of infants for treatment, and the decision of when and how to treat vary widely between centers. Our findings suggest the need for randomized, placebo-controlled trials of the effect of treatment of the PDA in preterm infants.     

Effects of ibuprofen and indomethacin on urinary antidiuretic hormone excretion in preterm infants treated for patent ductus arteriosus

OBJECTIVE: To compare the effects of intravenous ibuprofen and indomethacin for treatment of patent ductus arteriosus (PDA) on urinary antidiuretic hormone (ADH) excretion, as a cause of oliguria. STUDY DESIGN: Forty-four respiratory distress syndrome prematures (相似文献   

The effect of in utero exposure to indomethacin on the need for surgical closure of a patent ductus arteriosus in the neonate

OBJECTIVE: Our purpose was to determine the effect of in utero exposure to indomethacin on the need for surgical closure of a patent ductus arteriosus (PDA). STUDY DESIGN: Perinatal variables were compared between infants at <32 weeks who required surgical closure of PDA after failed medical management and those who did not. Statistical analysis was performed by Student t, Mann-Whitney, chi(2), and multiple logistic regression tests. RESULTS: Eight of 77 infants with PDA failed therapy and required surgery. Maternal demographics, gestational age, birth weight, and delivery route were similar in both groups. In utero exposure to indomethacin was more common in neonates requiring surgery versus those who did not, particularly when exposure was for >72 hours (50.0% vs 8.7%, odds ratio 10.5, 95% CI 1.6-72.1, P =.008). CONCLUSION: Need for surgical closure of PDA appears to be increased by in utero indomethacin exposure. These findings should be considered in the overall context of the risk versus benefits of tocolysis.     

Renal effects of ibuprofen for the treatment of patent ductus arteriosus in premature infants.

In recent years ibuprofen has been proposed for the treatment of patent ductus arteriosus (PDA) as it has been proved to be equally as effective as indomethacin and shows fewer cerebral blood flow, intestinal and renal hemodynamic effects. A number of studies and several meta-analyses comparing both drugs are now available that debate whether indomethacin or ibuprofen should be used for PDA prophylaxis or closure. This review examines the available knowledge on the specific issue of the effects of ibuprofen on kidney function, as improved renal tolerance is a major argument in favor of its use in the routine treatment of PDA. There is sufficient evidence to consider that ibuprofen, at the currently proposed dosing regimen, has a similar efficacy to indomethacin but is better tolerated by the neonatal kidney when employed for the treatment of established PDA. However, adverse effects of ibuprofen have been evidenced both in trials on the use of ibuprofen for the prevention of PDA and of intraventricular hemorrhage-periventricular hemorrhage (IVH-PVH), and in experimental studies on a neonatal, anesthetized animal model. Thus ibuprofen, as with other cyclooxygenase (COX) inhibitors, may not be exempt from causing renal adverse effects, especially in circumstances when renal prostaglandin activation is maximal (i.e., when administrated early after birth, in more immature patients and in certain situations such as in the anesthetized rabbit). However, although the issue has been addressed extensively in the last decades, there is insufficient evidence that therapeutic intervention in PDA is beneficial in terms of mortality or clinically significant morbidity outcomes. Studies aimed at resolving this key issue are still needed.     

Indomethacin therapy for patent ductus arteriosus in premature infants: efficacy of a dosing strategy based on a second-dose peak plasma indomethacin level and estimated plasma indomethacin levels

The objective of this study was to determine the rate of patent ductus arteriosus (PDA) closure in premature infants using an adjustable indomethacin (INDO) dosing strategy, based on a second-dose peak plasma INDO level. We conducted a retrospective review of the medical records of premature infants that were treated with INDO for a PDA, had a second dose peak plasma NDO levels, and followed predetermined guidelines for INDO dosing adjustments, over a 4-year period (1995 to 1998). Of 103 infants treated with the adjustable INDO dosing strategy, 66 (64%) achieved PDA closure whereas 37 (36%) did not. No differences in the second-dose peak plasma INDO levels (830 +/- 339 versus 702 +/- 381 ng/mL), day of life treatment was started (4 +/- 3 versus 4 +/- 2 days), or the number of doses of INDO received (4 +/- 1 versus 5 +/- 2 dose) were observed between responders and nonresponders. However, fourth-dose peak plasma INDO levels, which were available from 38 of 66 (57%) of the responders and 20 of 37 (54%) of the nonresponders, were lower in nonresponders (1553 +/- 413 versus 1829 +/- 609 ng/mL, p < 0.05). Patient demographics, including birth weight and gestational age, were similar between these groups. Using an adjustable INDO dosing strategy, based on a second-dose peak plasma INDO level and estimated plasma levels, PDA closure rates of 64% can be achieved. Although a clear relationship between INDO plasma levels and PDA closure was evident form this study, the rate of PDA closure in our study was lower than has been observed in studies with serial plasma INDO level monitoring.     

Indomethacin for patent ductus arteriosus closure. Application of serum concentrations and pharmacodynamics to improve response

Indomethacin dosing for patent ductus arteriosus closure has been standardized despite wide interpatient variability in indomethacin pharmacokinetics. We compared a novel indomethacin dosing approach using individual pharmacokinetic and pharmacodynamic information (group A) with a control group from our institution (group B) and a level 3 university-based intensive care nursery (group C) who were dosed using current dosing guidelines. Permanent patent ductus arteriosus closure was achieved in 27 of 28 (96.4%) group A patients, 10 of 16 (62.5%) group B patients, and 7 of 13 (52.8%) group C patients. Success rates were significantly higher in group A than Groups B and C (P less than .02). Renal toxicity was the only toxicity reported in any group. The major manifestations of renal toxicity, ie, urine output below 1 mL/kg/h or increased serum creatinine by greater than or equal to 0.5 mg/dL, occurred in none of the group A patients but in seven (43.8%) group B and eight (61.5%) group C patients. Renal toxicity was significantly greater in groups B and C than group A (P less than .02). A pharmacodynamic concentration versus response curve was developed and proved predictive of patent ductus arteriosus closure rates in previous studies where indomethacin concentration versus response data were available. Serum concentration monitoring is a valuable adjunct to indomethacin therapy for patent ductus arteriosus closure, especially when a pharmacodynamic approach is used.     

Early screening and treatment of "silent" patent ductus arteriosus in prematures with RDS

From January 1987 to December 1989, prematures with RDS weighing 1750 g or less admitted to the Neonatal Intensive Care Unite (NICU) were submitted from the third postnatal day to serial two-dimensional and pulsed Doppler (ATL MK 600) echocardiographic evaluation for "silent" patent ductus arteriosus (PDA). PDA was diagnosed in 36/175 prematures with RDS (20.5%). Thirty patients had indomethacin treatment and the PDA closed completely in 27 (90%); five needed a second course of indomethacin, that was effective in two (40%). Four RDS patients (4/36-11%) already weaned from the respirator, needed supplemental oxygen. The three non-responders and six other prematures with counterindications to the drug underwent surgical ligation (25%). As historical control, we retrospectively evaluated the population of preterm infants with RDS weighing less than or equal to 1750 g treated for hemodynamically significant PDA during three previous years before the screening protocol; in this group the echocardiographic and Doppler evaluations were done when congestive heart failure and pulmonary edema were clinically evident. In comparison, we found a reduced incidence of prematures with RDS treated for PDA, 7/120 (5.8%) a higher age at medical treatment (9 +/- 1.4 vs 4.4 - 2.3 days) and a larger prevalence of patients underwent ductal ligation (71.4%). These data show that early screening and treatment of "silent" PDA may result advantageous to improve the efficacy (90%) of indomethacin, in a critical time for the recovery of RDS, and furthermore decreasing the need of surgical ligation.     

The association of platelets with failed patent ductus arteriosus closure after a primary course of indomethacin or ibuprofen: a systematic review and meta-analysis

Objective: To conduct a meta-analysis of the association of platelet counts and pharmacotherapeutic failure in preterms with a patent ductus arteriosus (PDA).

Methods: MEDLINE, Embase, Science Citation Index, abstracts and conference proceedings were searched, and principal authors contacted. Included studies reported indomethacin or ibuprofen use for PDA closure, compared a group which failed treatment versus a group which did not and reported the association between platelet counts and indomethacin or ibuprofen failure. Two reviewers independently screened results and assessed methodological quality using the Newcastle-Ottawa Scale. Results are expressed as mean difference in platelet counts and summary odds ratios (OR) using a random effects model.

Results: 1105 relevant studies were identified; eight involving 1087 preterms were included. Platelet counts were significantly lower in infants who failed pharmacotherapy (Meandifference:–30.88?×?10⁹/L; 95% CI:–45.69?×?10⁹,–16.07?×?10⁹/L; I2?=?24%; p_{heterogeneity?}=_?0.24). Similar results were obtained based on either pharmacotherapeutic agent. Treatment failure was also significantly associated with pre-treatment thrombocytopenia (summary OR:1.75; 95% CI:1.23–2.49, I2?=?36%, p_{heterogeneity?}=_?0.20).

Conclusions: Platelet counts are significantly lower in preterms who fail primary treatment for PDA. Pre-treatment thrombocytopenia is associated with higher odds of failure. Further cohort studies reporting platelet counts in prostaglandin inhibitor failure are needed for meta-analyses to firmly establish or refute a stronger association.     

Diagnosis of patent ductus arteriosus by a neonatologist with a compact, portable ultrasound machine.

OBJECTIVES: To conduct a pilot study assessing a neonatologist's accuracy in diagnosing patent ductus arteriosus (PDA) using compact, portable ultrasound after limited training. STUDY DESIGN: Prospective study of premature infants scheduled for echocardiography for suspected PDA. A neonatologist with limited training performed study exams before scheduled exams. Sensitivity and specificity were calculated, compared to the scheduled echocardiogram interpreted by a cardiologist. RESULTS: There were 24 exams. Compared to the scheduled exam, the neonatologist's exam had sensitivity 69% (95% confidence interval (CI), 41 to 89%) and specificity 88% (95% CI, 47 to 99%). When a cardiologist interpreted the study exams, the sensitivity was 87% (95% CI, 60 to 98%) and specificity 71% (95% CI, 29 to 96%). CONCLUSION: A neonatologist with limited training was able to detect PDA with moderate success. A more rigorous training process or real-time transmission with cardiologist interpretation may substantially improve accuracy. Institutions with experienced technicians and on-site pediatric cardiologists may not gain from intensive training of neonatologists, but hospitals where diagnosis and treatment of PDA would be delayed may benefit from such processes.