Ductus Arteriosus In Preterm Infants Research Articles

Learning to live with patency of the ductus arteriosus in preterm infants

Treatment of persistent patency of the ductus arteriosus in preterm infants remains heterogeneous and controversial. Routine early treatment to induce ductal closure is not beneficial, but the potential criteria for, timing of, methods for and benefits of later ductal closure have not been determined. Management strategies for infants awaiting spontaneous closure or meeting criteria for treatment may be based on pathophysiological considerations but require evaluation in clinical trials. Better diagnostic tools allowing the identification of infants who might benefit from ductal closure, supplemented by data from clinical trials confirming realization of that potential, are urgently needed.

Impaired Lung Function After Intubation and Mechanical Ventilation for Surgical Ligation of the Ductus Arteriosus in Preterm Infants

Significant patent ductus arteriosus (PDA) in the preterm infant has been associated with pulmonary edema and impaired gas exchange. Therefore, surgical ligature of the DA may be required. However, the effects of intubation and mechanical ventilation on the PDA-induced lung dysfunction presently are unknown. The aim of the study was to investigate whether intubation and mechanical ventilation alter pulmonary function in the preterm infant with significant PDA. A prospective study. The neonatal intensive care unit and department of anesthesiology in a university hospital. Preterm infants <32 weeks' gestational age treated with nasal continuous positive airway pressure (NCPAP) and requiring mechanical ventilation for undergoing surgical DA ligature. Respiratory, Doppler echocardiographic parameters, and chest x-ray transparencies of the lungs were measured during NCPAP and 2 hours after intubation and starting mechanical ventilation. Twenty preterm infants (gestational age = 27 ± 1 wk, birth weight = 950 ± 140 g) were included. Heart rate, O(2) need, PaCO(2), and plasma lactate concentrations were significantly higher after intubation. The mean oxygenation index increased from 1.5 ± 0.6 to 7.2 ± 3 (p < 0.05). The overall transparencies of the lungs decreased after intubation. DA diameter, shortening fraction of the left ventricle, left pulmonary artery blood flow velocities, and left atrium/aorta did not change. In preterm infants with significant PDA, intubation and mechanical ventilation before surgical DA ligation may increase the O(2) need and PaCO(2) and may promote lung edema formation. Mechanical ventilation-induced impairment in lung function is not associated with a change in pulmonary or systemic circulation or DA flow. Special care should be taken to prevent respiratory failure when intubation and mechanical ventilation are required for undergoing surgical DA ligation in the preterm infant.

Second course of oral ibuprofen in closure of patent ductus arteriosus in preterm infants: Is it safe?

Second course of oral ibuprofen in closure of patent ductus arteriosus in preterm infants: Is it safe?

Current management of patent ductus arteriosus in premature infants among neonatologists and pediatric cardiologists

Current management of patent ductus arteriosus in premature infants among neonatologists and pediatric cardiologists

949 Risk of Bronchopulmonary Dysplasia (BPD) is Increased After Surgical Ligation of Ductus Arteriosus in Preterm Infants

949 Risk of Bronchopulmonary Dysplasia (BPD) is Increased After Surgical Ligation of Ductus Arteriosus in Preterm Infants

646 Impact of Ductal Size on Successful Medical Closure of Patent Ductus Arteriosus in Preterm Infants

Cyclooxygenase inhibitors (CI) are widely accepted treatment for hemodynamically significant persistant ductus arteriosus (HsPDA) of the preterm infant (PI) Failure of medical closure of PDA is associated with more complications.Objective: Analyze the effect of PDA diameter on medical treatment success in PI.Methods: retrospective study of very PI (≤32 GW) admitted with respiratory distress requiring mechanical ventilation in the first 24 hours of life with a diagnosed HsPDA Failure of treatment was defined by persistance of HsPDA after complete course of CI treatment.Results: among 217 PI, 54 patients (25%) were diagnosed with hemodynamically significant PDA Five patients died before CI treatment and 49 PI were treated 12 patients (25%) had failed to medical treatment, 4 of them had a chirurgical ligation, 6 died with a significant PDA and 2 were discharged with a pauci-symptomatic PDA Mean anterior PDA diameter in the Fail group (3,1 mm ± 1,1) was higher than that in the Success group (2,3 mm± 1,2; p:0,001) When using an index of PDA diameter/birth weight, a cuttoff value of less than 2,8 mm/kg predicts medical PDA closure in 81% of patients Others risks factors associated with failure treatment were low gestational age and postnatal age ≥ 72 hours at initiation of treatment.Conclusion: In preterm infants with HsPDA, mean anterior PDA diameter reported to the birth weight > 2,8mm/kg predict failure of medical treatment Delay of CI treatment and low gestational age are also a great risk factors for failure of medical management of PDA.

AO-37. Relationship of cord blood vascular endothelial growth factor with patent ductus arteriosus in premature infants

AO-37. Relationship of cord blood vascular endothelial growth factor with patent ductus arteriosus in premature infants

615 Changes in Myocardial Velocities and Haemodynamics After Surgical Ligation of the Patent Ductus Arteriosus in Preterm Infants

Background and aims: The circulatory effects of surgical ligation of a haemodynamically significant ductus arteriosus (DA) in a preterm infant are poorly understood. This study aimed to measure changes in myocardial velocities, as an assessment of ventricular function, following ligation of the DA, using the new technique of Pulsed wave tissue Doppler imaging (PWTDI). Methods: Echocardiograms were performed within 24 hours before and after DA ligation. Myocardial velocities were measured in the basal left and right ventricles and inter-ventricular septum (RV, LV & IVS). Duct size and flow, left atrium:aortic valve ratio (LA:Ao), and left ventricular output (LVO) were also measured. Results: Data was collected in five infants, median weight 1.4 (range 0.7-2.1) kg, gestation 26.0 (24.4- 30.3) weeks, age 25 (22-50) days. Infants were ventilated, none received inotropes. PDA diameter was 0.30 (0.20-0.33) cm, ductal flow was left to right. Following DA ligation, LVO was reduced (mean [SD], 335[118] vs. 258 [63] mL/kg/min). LA:Ao was reduced but remained above normal limits (2.2[0.3] vs.1.9[0.4]). There was a trend of reduced mean LV myocardial velocities after DA ligation, however there was considerable variation between infants (Figure 1). Conclusions: DA ligation acutely reduces LVO, altering loading conditions in the left heart. Reduced mean myocardial velocities in the LV may represent a reduction in both systolic and diastolic function after DA ligation. Individual variation in myocardial response may explain why some, but not all, infants experience cardio-respiratory instability after DA ligation.

206 Nt Pro-Bnp, Ngal, and H-Fabp are Indicators of Hemodynamic Relevance of Patent Ductus Arteriosus in Preterm Infants

Background and aims: Patent ductus arteriosus (PDA) is the most common functional cardiovascular disease of preterm infants. Hemodynamic relevance for organs and circulation can neither be derived from clinical nor from echocardiographic criteria. The aim of the present study was to establish non-invasive parameters which reflect perfusion-dependent consequences of the ductus for the organism of the preterm infant. Methods: Urinary protein levels of NT pro-BNP, NGAL, and H-FABP were measured and correlated with the necessity of therapeutic interventions for PDA. In a group of 38 preterm infants with a birth weight of less than 1500g, the protein concentrations in urine were tested on day 0-1, 2-4, and 6-8 by ELISA methodology. 12 of 38 infants required therapeutic interventions according to current treatment standards. Results: Infants receiving an intervention for PDA (either ibuprofen treatment of ligation) showed significantly higher levels of NT pro-BNP, NGAL, and H-FABP at all time points except for NT pro-BNP on day 0. Infants requiring a second or third course of ibuprofen had significantly higher levels of H-FABP and NGAL. In all samples the concentration of the three proteins NT pro-BNP, NGAL, and H-FABP correlated positively with each other. Conclusions: The present study shows that measurement of urinary proteins is a powerful and non-invasive method to quantify the effect of the PDA on the organism in preterm infants. Furthermore our data show that NGAL and H-FABP can be used to predict the necessity of pharmaceutical or surgical treatment of PDA.

Efficacy and tolerability of enteral formulations of ibuprofen in the treatment of patent ductus arteriosus in preterm infants

Background: The persistence of a patent ductus arteriosus (PDA) in preterm infants complicates their clinical course and may contribute to increased morbidity. Intravenous preparations of ibuprofen constitute one of the standard therapies for closure of a PDA. However, the unavailability of intravenous ibuprofen in certain regions of the world and the availability of inexpensive oral preparations has led to off-label nasogastric administration of oral ibuprofen in preterm infants with PDA. Objective: This article reviews and comments on the evidence for the enteral use of oral formulations of racemic ibuprofen for PDA closure in preterm infants, with a focus on the risk of necrotizing enterocolitis (NEC). Methods: MEDLINE, Current Contents, and Google Scholar were searched in April 2010 for trials of enteral ibuprofen in the treatment of PDA in preterm or low-birth-weight infants using the terms treatment, pharmacokinetics, ibuprofen, oral, enteral, patent ductus arteriosus, PDA, preterm, premature, low birth weight, infant, and newborn. Relevant congress Web sites were also searched for relevant abstracts. Results: The literature search identified 2 pharmacokinetic studies involving 32 infants and 13 clinical efficacy studies involving 306 infants treated with enteral ibuprofen. The clinical studies reported some benefit for enteral ibuprofen relative to the comparators. However, these studies had methodologic limitations, including small numbers of subjects, lack of blinding, inclusion of preterm infants with a higher gestational age, customized treatment regimens, and second-order statistical error that prevented conduct of a systematic review. When the results of all studies were pooled, NEC was reported in a total of 46 of 281 infants (16%) receiving enteral ibuprofen and 21 of 83 infants (25%) receiving indomethacin. This rate of NEC with enteral ibuprofen was twice that reported for intravenous ibuprofen in a recent meta-analysis (27/356 [8%]). Conclusions: The evidence supporting the off-label use of enteral ibuprofen for PDA in preterm infants is weak. Well-designed, appropriately powered pharmacologic and controlled clinical studies are needed before use of enteral ibuprofen can be recommended. In countries where an intravenous formulation of racemic ibuprofen is approved, off-label use of enteral racemic ibuprofen cannot be supported.

Minimally invasive surgical closure of patent ductus arteriosus in premature infants: a novel approach.

Recent advancement of minimally invasive cardiac surgical procedures have prompted the use of minimal incisions to perform operations on patients with congenital heart defects. In this report, we describe a new technique for closure of a patent ductus arteriosus, using an anterior extrapleural approach. We present our technique and results in five low-weight infants. This approach is safe and effective, shortens hospital stay, and is less invasive than classical approaches.

Antenatal Indomethacin Tocolysis Is Associated With an Increased Need for Surgical Ligation of Patent Ductus Arteriosus in Preterm Infants

ObjectiveTo examine the effect of antenatal indomethacin (AI) exposure on the incidence, response to postnatal indomethacin (PI), and need for surgical ligation of patent ductus arteriosus (PDA) in preterm infants. MethodsWe performed a retrospective matched cohort study of infants born at < 30 weeks' gestation after exposure to AI administered because of preterm labour. Control subjects were infants unexposed to AI but with similar gestational age and birth weight. We compared the incidence of PDA, response to treatment with PI, and surgical PDA ligation rate between the two groups. ResultsThere was no difference in the incidence of PDA between AI infants (67.6%) and control subjects (66.6%). Only 22 of 54 (41%) infants in the AI group responded to PI therapy for symptomatic PDA closure, compared to 34 of 52 (65%) infants in the control group (P= 0.012). Thirty-two (59%) infants in the AI group required surgical PDA ligation after indomethacin therapy, compared with 18 infants in the control group (35%) (P= 0.01). Multivariate logistic regression analysis showed that AI exposure was independently associated with surgical ligation of PDA (adjusted odds ratio 3.07; 95% CI 1.46 to 6.45). ConclusionIn infants born preterm (<30 weeks) with a PDA, antenatal exposure to indomethacin was associated with an increased rate of therapeutic failure of PI and an increased rate of surgical PDA ligation compared with controls without such antenatal exposure.

Effect of ibuprofen on bilirubin–albumin binding in vitro at concentrations observed during treatment of patent ductus arteriosus

Background In vitro studies have shown that ibuprofen (IBU) may interfere with bilirubin–albumin binding at concentrations of 100 µg/mL and above. Objectives The present study evaluates the in vitro bilirubin displacement over the range of IBU plasma concentrations observed in vivo during curative treatment of patent ductus arteriosus in preterm infants. Methods Considering that individual plasma concentrations obtained during the clinical development of IBU in preterm infants were ranging between 10 and 70 µg/mL and exceptionally above 100 µg/mL, we used the modified peroxidase method to determine total and unbound bilirubin concentrations without IBU and with IBU over this specific concentration range. Results Total bilirubin and albumin concentrations were respectively 6.6 mg/dL and 2.87 g/dL in pooled newborn plasma. No displacement of bilirubin from its albumin binding sites by IBU was observed over a range of concentrations from 10 to 100 µg/mL. Only a concentration of 200 µg/mL significantly increased the unbound bilirubin by 1.5-fold ( p = 0.0008). Conclusions This in vitro study confirms displacement of bilirubin by a high IBU concentration of 200 µg/mL, however it retrieves no significant displacement over a range of concentrations up to and including 100 µg/mL, i.e. within the range of in vivo concentrations at the recommended dose regimen.

Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?

Medical and surgical interventions are widely used to close a persistently patent ductus arteriosus in preterm infants. Objective evidence to support these practices is lacking, causing some to question their usage. Emerging evidence suggests that treatments that close the patent ductus may be detrimental. This review examines the history of and evidence underlying these treatments. Neither individual trials, pooled data from groups of randomized-controlled trials, nor critical examination of the immediate consequences of treatment provide evidence that medical or surgical closure of the ductus is beneficial in preterm infants. These conclusions are supported by sufficient evidence. Neither continued routine use of these treatments nor additional clinical trials using similar designs seems to be justified. A definitive trial, comparing current standard management with novel strategies not primarily intended to achieve ductal closure, may be necessary to resolve doubts regarding the quality or conduct of prior studies.

A Clinical Staging System Does Not Predict the Presence of a Haemodynamically Significant Patent Ductus Arteriosus in Preterm Infants

A Clinical Staging System Does Not Predict the Presence of a Haemodynamically Significant Patent Ductus Arteriosus in Preterm Infants

Is There an Optimal Timing for Surgical Ligation of Patent Ductus Arteriosus in Preterm Infants?

Is There an Optimal Timing for Surgical Ligation of Patent Ductus Arteriosus in Preterm Infants?

Is There an Optimal Timing for Surgical Ligation of Patent Ductus Arteriosus in Preterm Infants?

We sought to define the variables associated with hospital outcome in preterm infants with patent ductus arteriosus (PDA) and identify the optimal timing for PDA closure to improve hospital outcome. Included were 201 premature babies (< or = 32 weeks gestational age), from January 2001 to June 2007, with PDA who received primary medical treatment with ibuprofen. Number of ibuprofen cycles, gestational age, body weight, and presence of symptomatic hypotension requiring vasoactive/inotropic drugs were related to hospital outcome, including hospital mortality, presence of necrotizing enterocolitis, acute renal failure, intraventricular hemorrhage, retinopathy and bronchopulmonary dysplasia at week 36. Data were analyzed with a logistic regression model. Medical treatment was effective in 149 patients (75%), but 52 (25%) required surgical ligation after medical treatment failed. They had younger gestational age (25 weeks [IQR, 24 to 27 weeks] vs 27 weeks [IQR, 25 to 28 weeks], p < 0.0001), lower body weight at birth (730 g [IQR, 595 to 915 g] vs 840 g [IQR, 670 to 1016], p = 0.05), and a higher incidence of symptomatic hypotension (38 of 52 [73%] vs 56 of 149 [38%], p < 0.0001) than patients who responded to ibuprofen. More than two cycles of ibuprofen was significantly associated with an increased risk for bronchopulmonary dysplasia (odds ratio [OR], 2.81; p = 0.03) and acute renal failure (OR, 3.81; p = 0.09). The prolonged patency of the ductus arteriosus in preterm infants is related to an increased morbidity. Surgical ligation of PDA is a safe and effective treatment and should be done soon after two complete cycles of ibuprofen, especially in selected patients, to improve clinical outcome.

Delayed Neonatal Closure of the Ductus Arteriosus Following Early in utero Exposure to Indomethacin in the Rat

Background: Indomethacin is used to close the patent ductus arteriosus in premature infants and for tocolysis of preterm labor. Clinically and experimentally, early in utero exposure to indomethacin induces the paradoxical delay of postnatal closure of the ductus arteriosus. Objectives: To clarify the pharmacological nature of the delay of closure of the ductus arteriosus in the rat. Methods: We studied early in utero exposure to indomethacin (dose and timing) in addition to other drugs, inducing a delay in postnatal ductal closure. Pregnant rats at near term were studied by cesarean section on gestational day 21 (D21), incubated in room air at 33°C, followed by rapid whole-body freezing. Results: The delay in closure of the ductus arteriosus was dose dependent. A large dose of indomethacin (10 mg/kg) 1 or 2 days before birth induced a delay of 3–4 times. A timing study revealed maximum delay with administration of indomethacin 2 days before birth and minimum delay with administration 5 days before. Aspirin, ibuprofen, the selective COX1 inhibitor SC 560, the selective COX2 inhibitor rofecoxib and a prostaglandin EP₄ receptor blocker, ONO-208, all delayed neonatal ductal closure following maternal administration on D19 and D20. Conclusions: The delay by indomethacin was dose dependent. The maximum delay was induced by 2 doses of 10 mg/kg indomethacin on D19 and D20. The delay was induced by a decreased stimulus to the prostaglandin EP₄ receptor system in the last 2 days in utero. The delay was temporary with recovery 3 days or more after exposure.

Early or Late Surgical Ligation of Medical Refractory Patent Ductus Arteriosus in Premature Infants

Optimal time to surgical ligation of patent ductus arteriosus (PDA) in very-low-birth-weight (< 1500 g) premature infants remains an area of controversy. We compared the outcomes of early or late ligation of medical refractory PDA in very-low-birth-weight premature infants. Fifty-six infants underwent surgical closure of PDA after failure of or having contraindications to medical treatment. Thirteen infants were in the early ligation (< or = 14 days) and 43 in the late ligation (> 14 days) groups. Basic clinical features, major morbidity of prematurity and mortality were compared. Clinical features and major outcomes were similar. The early ligation group had earlier onset of symptomatic PDA (5.7 +/- 1.6 days vs. 8.1 +/- 3.6 days, p = 0.024), and fewer days of total parenteral nutrition (TPN) (39.6 +/- 13.9 days vs. 60.4 +/- 31.4 days, p = 0.025) and ventilator use (11.1 +/- 6.7 days vs. 18.6 +/- 10.5 days, p = 0.019). Early ligation of medical refractory PDA in very-low-birth-weight premature infants improves enteral feeding tolerance and reduces TPN and ventilator use, but long-term benefits need further investigation.

Persisterende ductus arteriosus hos for tidlig fødte barn

Patent ductus arteriosus in premature infants has often been treated because of its association with worsening of pulmonary disease and complications such as bronchopulmonary dysplasia. This view has now been challenged.Relevant publications have been identified from review articles in international peer-reviewed journals. The articles have been retrieved through searches in the PubMed and Cochrane-databases.Recent research has led to a new understanding of patent ductus arteriosus - a shift of paradigm has occurred. The condition implies that a shunt enables blood to flow from right to left in the first postnatal days (when pulmonary arterial pressure is high), and left to right in cases where significant pulmonary disease is present. The increased pulmonary blood flow improves oxygenation, and the condition should be considered as physiological in small premature infants. A patent ductus arteriosus does not worsen concomitant pulmonary disease or increase the risk of bronchopulmonary dysplasia, intraventricular hemorrhage, necrotising enterocolitis or other complications.Treatment of a patent ductus arteriosus with COX-inhibitors such as indomethacin and ibuprofen, increases the risk for bronchopulmonary dysplasia without reducing other complications or death. A large patent ductus arteriosus has significant hemodynamic effects and should be treated with fluid restriction, diuretics and inotropic drugs before closure is considered. Surgical closure of a patent ductus arteriosus is linked to neurosensory impairment in survivors.