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.

Perfusion Index-Bedside Diagnosis of Hemodynamically Significant Patent Ductus Arteriosus.

BACKGROUND: Patent ductus arteriosus (PDA) is a significant problem in preterm babies <34 weeks old. Echocardiogram (echo) is the gold standard for diagnosing PDA. Perfusion index (PI) using a pulse oximeter could aid in diagnosing a hemodynamically significant PDA (HsPDA). OBJECTIVE: To evaluate the accuracy of delta-PI (ΔPI; pre-ductal - post-ductal PI) in diagnosing HsPDA in preterm babies <34 weeks old. DESIGN: Prospective analytical cross-sectional (observational) study. METHODS: Preterm infants <34 weeks old (n = 27) were enrolled in the study after parental consent. ΔPI was calculated on Days 1 and 3. Babies are categorized into two groups-HsPDA and no HsPDA based on echo on Day 3. RESULTS: The mean gestational ages were 30.4 ± 1.9 (HsPDA) and 31.7 ± 1.6 weeks (no HsPDA), and birth weights were 1.23 ± 0.32 kg and 1.43 ± 0.34 kg, respectively (p > 0.05). Ten infants had HsPDA. The ΔPI values in Groups A and B differed significantly on Days 1 and 3 (Day 1: 1.06 ± 0.3 vs. 0.54 ± 0.2 and Day 3: 1.11 ± 0.15 vs. 0.57 ± 0.3). The area under the receiver operating characteristic curve was significant for ΔPI on Days 1 and 3. The ΔPI > 0.85 on Day 1 and > 0.95 on Day 3 had a sensitivity and specificity of 80% and 94% and 80% and 88.2%, respectively, for diagnosing HsPDA. CONCLUSION: ΔPI is a useful, simple parameter, which could help in the assessment of PDA in preterm babies.

N-terminal pro-brain natriuretic peptide measurements in hemodynamically significant patent ductus arteriosus in preterm infants.

OBJECTIVES: Evaluate the role of NT-proBNP levels in Preterm neonates suffering from PDA and used as a screening tool for predicting HsPDA and guiding physicians to consider early echocardiographic evaluation. METHODS: This is a monocentric prospective blind study which was conducted at Arar Central Hospital, Ar'ar, Saudi Arabia, during the period between Jan 2014 to June 2014. Thirty-three (33) preterm infants born at less than 31 weeks of gestation or weighing less than 1200 g at birth infants were initially enrolled during a 6-month period. Blood samples were collected along with routine blood tests on days 1, 2, 3, and 7 of life for NT-proBNP analysis. Two echocardiographies were systematically performed on day two of life to ascertain about the status of Ductus Arteriosus. RESULTS: The Plasma NT-proBNP levels were high on day one of life and decline from day three to day seven of life except in those infants with significant hsPDA. Plasma NT-proNBP levels on day 2 of infants in the HsPDA group were significantly higher (<0.001) than those in non-HsPDA group. Echocardiogram parameters indicates the significant difference (p<0.002) in Left Atrial and Aortic ratio (LA/AO), Interventricular septum thickness (P<0.03), Left ventricular posterior wall thickness (p<0.05), diastole PDA gradient (p<0.005) between HsPDA and non-HsPDA. CONCLUSIONS: Plasma NT-proBNP level peaked during the first few days after birth and declined rapidly within a week. Therefore, its level may have a role as a screening tool to predict HsPDA and provide more information regarding its spontaneous closure or otherwise.

Paracetamol for patent ductus arteriosus in preterm infants: a UK national survey.

INTRODUCTION: Evidence is emerging that paracetamol is a safe and effective alternative therapy for haemodynamically significant patent ductus arteriosus (hsPDA). Although there is no consensus opinion on its routine use for PDA in preterm infants, paracetamol is being used increasingly in many centres to treat hsPDA. OBJECTIVE: We conducted a national survey to review the current practice in the UK and the prevalence of paracetamol use for hsPDA closure in preterm infants. METHOD: A web-based and telephone survey on the use of paracetamol for hsPDA closure in preterm infants was conducted. All neonatal intensive care and local neonatal units across the UK were contacted between May and August 2018. RESULTS: 98% (143/146) neonatal units responded. The first-line medication for hsPDA closure was ibuprofen in 92% (131/143) units. 33% (47/143) of units used paracetamol; three units used it as first-line. The dose and duration of paracetamol varied greatly among the units with a dose of 15 mg/kg 6 hourly in 62% (29/47) units and a duration of 3 and 5 days in 33% (14/42) and 31% (13/42) of units, respectively. 44% (19/43) of units did routine blood investigations using paracetamol for monitoring patients on treatment and 21% (9/43) took paracetamol level in addition to other tests. CONCLUSION: 33% of the neonatal units across the UK offered paracetamol to treat hsPDA in preterm infants. Currently, there is a variation in practice regarding the dose, duration of paracetamol and monitoring of infants during its use for hsPDA closure. One strategy would be to develop national guidance once strong evidence is established to support its routine use for hsPDA in preterm infants.

Decreased plasma levels of PDGF-BB, VEGF-A, and HIF-2α in preterm infants after ibuprofen treatment.

Introduction: Ibuprofen is one of the most common non-steroidal anti-inflammatory drugs used to close patent ductus arteriosus (PDA) in preterm infants. PDA is associated with bronchopulmonary dysplasia (BPD), while PDA closure by ibuprofen did not reduce the incidence of BPD or death. Previous studies have indicated an anti-angiogenesis effect of ibuprofen. This study investigated the change of angiogenic factors after ibuprofen treatment in preterm infants. Methods: Preterm infants with hemodynamically significant PDA (hsPDA) were included. After confirmed hsPDA by color doppler ultrasonography within 1 week after birth, infants received oral ibuprofen for three continuous days. Paired plasma before and after the ibuprofen treatment was collected and measured by ELISA to determine the concentrations of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor A (VEGF-A), and hypoxia-inducible factor-2α (HIF-2α). Results: 17 paired plasma from infants with hsPDA were collected. The concentration of PDGF-BB and VEGF-A significantly decreased after ibuprofen treatment (1,908 vs. 442 pg/mL for PDGF-BB, 379 vs. 174 pg/mL for VEGF-A). HIF-2α level showed a tendency to decrease after ibuprofen treatment, although the reduction was not statistically significant (p = 0.077). Conclusion: This study demonstrated decreased vascular growth factors after ibuprofen exposure in hsPDA infants.

Objective Assessment of Physiologic Alterations Associated With Hemodynamically Significant Patent Ductus Arteriosus in Extremely Premature Neonates.

Delay in closure of ductus arteriosus in postnatal life may lead to serious consequences and complications in an extremely premature neonate secondary to hemodynamic alterations in regional blood flow pattern in various organs. Despite the widespread recognition amongst neonatologists to identify a hemodynamically significant patent ductus arteriosus (hsPDA) early in the postnatal course, there is lack of consensus in its definition and thus the threshold to initiate treatment. Echocardiographic assessment of PDA shunt size and volume combined with neonatologists' impression of clinical significance is most frequently used to determine the need for treatment of PDA. Common clinical signs of hsPDA utilized as surrogate for decreased tissue perfusion may lag behind early echocardiographic signs. Although echocardiogram allows direct assessment of PDA shunt and hemodynamic alterations in the heart, it is limited by dependence on pediatric cardiologist availability, interobserver variation and isolated time point assessment. Electrical cardiometry (EC) is a non-invasive continuous real time measurement of cardiac output by applying changes in thoracic electrical impedance. EC has been validated in preterm newborns by concomitant transthoracic echocardiogram assessments and may be beneficial in studying changes in cardiac output in premature newborns with hsPDA. Alterations in perfusion index derived from continuous pulse oximetry monitoring has been used to study changes in cardiac performance and tissue perfusion in infants with PDA. Near infrared spectroscopy (NIRS) has been used to objectively and continuously assess variations in renal, mesenteric, and cerebral oxygen saturation and thus perfusion changes due to diastolic vascular steal from hsPDA in preterm neonates. Doppler ultrasound studies measuring resistive indices in cerebral circulation indicate disturbance in cerebral perfusion secondary to ductal steal. With recent trends of change in practice toward less intervention in care of preterm newborn, treatment strategy needs to be targeted for select preterm population most vulnerable to adverse hemodynamic effects of PDA. Integration of these novel ways of hemodynamic and tissue perfusion assessment in routine clinical care may help mitigate the challenges in defining and targeting treatment of hsPDA thereby improving outcomes in extremely premature neonates.

N-terminal pro-brain natriuretic peptide used for screening hemodynamically significant patent ductus arteriosus in very low birth weight infants: How and when?

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NTproBNP) appears to be a useful tool for diagnosing hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. However, a consensus for its application has not been reached. OBJECTIVE: The present study aims to evaluate the role of NTproBNP in predicting hsPDA in preterm infants, and explore the optimal cutoff value and testing-time. METHODS: A prospective blind study of 120 preterm infants with birth weights of < 1,500 g was conducted at the NICU of Peking University Shenzhen Hospital. Blood samples were successively collected on the first three days after birth for NTproBNP analysis. Echocardiographies were performed on day three of life to confirm the status of the ductus arteriosus. A receiver operating characteristic curve (ROC) analysis was performed to determine the ability of NTproBNP to recognize hsPDA. RESULTS: NTproBNP was significantly higher in infants with hsPDA, than in infants in the control group, on both day two (P < 0.001) and day three (P < 0.001). On day two, a NTproBNP cutoff value of 3,689.0 pmol/L offered an optimal predictive value for hsPDA, while on day three, the optimal cut-off value for hsPDA was 2,331.5 pmol/L. The investigators proposes day three of life (48-72 hours) as the optimal testing time. CONCLUSION: The NTproBNP biomarker during the early neonatal period can be a useful tool for screening and assessing hsPDA in premature infants, especially on day three of life.

Therapeutic strategy of patent ductus arteriosus in extremely preterm infants.

The ductus arteriosus is likely to close without treatment in most infants born at gestational age (GA) > 28 weeks (73%), and those with birth weight > 1000 g (94%). However, the rates of spontaneous ductal closure among less mature or smaller infants with respiratory distress syndrome are not known. Extremely preterm infants born at GA < 28 weeks are associated with a high risk of severe intraventricular hemorrhage (IVH) or pulmonary hemorrhage, which usually occur within 72 h after birth and affect mortality and long-term neurological development. These serious hemorrhagic complications may be closely related to hemodynamic changes caused by a hemodynamically significant patent ductus arteriosus (hs-PDA). While prophylactic indomethacin has been shown to reduce the rates of PDA, PDA ligation, severe IVH and early pulmonary hemorrhage, the available evidence does not support its prophylactic use in preterm infants. Symptomatic or late treatment is associated with lower success rate, and increased complications of a hs-PDA. The issue of "to treat or not to treat a PDA" is controversial. Considering the relationship between the effectiveness and timing of pharmacological treatment, early targeted treatment may be an alternative approach for the early identification of a hs-PDA in specific high-risk patient population, especially infants <26 weeks GA who are at the highest risk of severe IVH or pulmonary hemorrhage. Serial echocardiographic studies can be used to select patients who are candidates for early targeted medical treatment of hs-PDA. Surgical ligation of PDA, and transcatheter closure if proven to be safe, can be used as back-up therapy for patients who fail medical treatment and continue to have cardiopulmonary compromise.

Findings From Somatic and Cerebral Near-Infrared Spectroscopy and Echocardiographic Monitoring During Ductus Arteriosus Ligation: Description of Two Cases and Review of Literature.

Background: Preterm infants with hemodynamically significant patent ductus arteriosus (HsPDA) are exposed to low cerebral tissue oxygen saturation (rScO2) values. Additionally, infants requiring surgical ligation are at risk of further changes in cerebral oxygenation and postligation cardiac syndrome (PLCS). Previous studies have assessed the effect of PDA ligation on rScO2 with variable results. Cases description: In this report we analyse near-infrared spectroscopy (NIRS) and echocardiographic findings of two patients who underwent ligation of PDA and presented low cardiac output. Literature on regional tissue oxygenation saturation (rSO2) before and after PDA ligation was briefly reviewed. Discussion: Cerebral oxygenation values before and after PDA ligation may be influenced by gestational age, vasopressor use, ductal shunt volume, time of exposure HsPDA, chronological age and the presence of cerebral autoregulation. PLCS complicates 28-45% of all PDA ligations and is associated with higher mortality. Cerebral and somatic NIRS monitoring in the postoperative period may enhance the identification of PLCS at early stages. Conclusion: Cerebral oxygenation in the perioperative period of PDA ligation may be influenced by numerous clinical factors. Early detection of PLCS using multisite NIRS after ligation could prevent further alterations in cerebral hemodynamics and improve outcomes. A decrease in somatic-cerebral difference and/or a significant drop in somatic NIRS values may precede clinical signs of hypoperfusion. NIRS values should be interpreted as trends along with echocardiographic findings to guide goal directed interventions.

Oral indomethacin versus oral ibuprofen for treatment of patent ductus arteriosus: a randomised controlled study in very low-birthweight infants.

BACKGROUND: In low- and middle-income countries (LMIC), haemodynamically significant patent ductus arteriosus (hsPDA) is treated with oral indomethacin (IDC) and ibuprofen (IB) instead of intravenous formulations. No significant differences in efficacy have been reported. However, previous studies had small numbers of VLBW infants (<1500 g). OBJECTIVE: To evaluate the efficacy of oral IDC and IB for closing PDA in VLBW infants with a gestational age of 24-32 weeks. METHODS: This randomised controlled study enrolled 32 infants with hsPDA for treatment with either three doses of oral IDC or oral IB. Echocardiography was performed before and after treatment. RESULTS: Oral IDC was more effective than oral IB (65% vs. 27%, p = 0.03). This difference was attributable to the subset of extremely low-birthweight infants (<1000 g) in whom an hsPDA closed 78% of the time after oral IDC compared with 13% of those treated with oral IB (p = 0.01). In contrast, there was no difference in hsPDA closure rates between the study groups of infants with birthweights of 1000-1499 g. There was no significant difference between the drugs in clinical and laboratory measures of adverse effects, nor of other clinical outcomes Conclusion: Oral IDC was more effective than oral IB for closing PDA in VLBW infants, without significant differences in side-effects or short-term outcomes.

The high-risk factors of different severities of bronchopulmonary dysplasia (BPD) based on the national institute of child health and human development (NICHD) diagnosis criteria in 2018 / Os fatores de alto risco de diferentes gravidades de displasia broncopulmonar (DBP) com base no instituto nacional de saúde infantil e desenvolvimento humano (NICHD): critérios de diagnóstico em 2018

ABSTRACT Objective To investigate the clinical characteristics of preterm infants with different severities of bronchopulmonary dysplasia (BPD) and disclose the high-risk factors of exacerbating BPD. Methods Collection of clinical data of 91 preterm infants admitted to the NICU and diagnosed with BPD, categorized in groups according to the disease severity: 41 mild cases,, 24 moderate cases, and 26 severe cases. Comparison and analysis of perinatal risk factors, treatment, complications and prognosis of the infants with different severity degrees. Results The severe group had a higher proportion of infants with congenital heart disease (CHD) higher than the moderate group (P < 0.05), and a higher ratio of pneumonia and mechanical ventilation (MV) ≥ seven days than the mild group (P < 0.05). The severe group also presented higher reintubation incidence than both the mild and moderate groups (P < 0.05). The groups presented different (P < 0.05) incidence rates of hemodynamically significant patent ductus arteriosus (hsPDA) . Ridit analysis suggested that the premature infants (PIs) with hsPDA, multiple microbial pulmonary infections, or Klebsiella pneumoniae pneumonia had more severe illness. Conclusion CHD, hsPDA, MV ≥ seven days, reintubation, pneumonia, especially multiple microbial pulmonary infections, and Klebsiella pneumoniae pneumonia are correlated with the severity of BPD and can be used as BPD progression predictor.

RESUMO Objetivo Investigar as características clínicas de prematuros com diferentes gravidades de displasia broncopulmonar (DBP) e divulgar os fatores de alto risco para a DBP. Métodos Coleta de dados clínicos de 91 prematuros internados em UTIN com diagnóstico de DBP, categorizados em grupos de acordo com a gravidade da doença: 41 casos leves, 24 casos moderados e 26 casos graves. Foram feitas a comparação e a análise de fatores de risco perinatais, tratamento, complicações e prognóstico de lactentes com diferentes graus de gravidade. Resultados O grupo grave teve uma proporção maior de bebês com doença cardíaca congênita (DCC) do que o grupo moderado (p < 0,05) e com pneumonia e ventilação mecânica (VM) ≥ 7 dias do que o grupo leve (p < 0,05). O grupo grave também apresentou maior incidência de reintubação do que os grupos leve e moderado (p < 0,05). Os grupos apresentaram diferentes (p < 0,05) taxas de incidência de persistência do canal arterial hemodinamicamente significativa (PCAhs). A análise de ridit sugeriu que os bebês prematuros (BPs) com PCAhs, infecções pulmonares microbianas múltiplas ou pneumonia por Klebsiella pneumoniae tinham doenças mais graves. Conclusão DCC, PCAhs, VM ≥ 7 dias, reintubação, pneumonia, principalmente infecções pulmonares microbianas múltiplas, e pneumonia por Klebsiella pneumoniae estão correlacionadas com a gravidade da DBP e podem ser usadas como preditoras de progressão da DBP.