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Pediatrics Nov 2020Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by... (Review)
Review
Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (<26 + 0/7 weeks' gestation, <750 g birth weight), (2) early targeted therapy of PDA in selected preterm infants at particular high risk for PDA-associated complications, and (3) PDA ligation, catheter intervention, or oral paracetamol may be considered as rescue options for hsPDA closure. The impact of catheter-based closure of hsPDA on clinical outcomes should be determined in future prospective studies. Finally, we provide a novel treatment algorithm for PDA in preterm infants that integrates the several treatment modalities in a staged approach.
Topics: Algorithms; Ductus Arteriosus, Patent; Humans; Infant, Newborn; Infant, Premature
PubMed: 33093140
DOI: 10.1542/peds.2020-1209 -
Pediatrics and Neonatology Apr 2020The 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... (Review)
Review
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.
Topics: Acetaminophen; Ductus Arteriosus, Patent; Echocardiography; Humans; Indomethacin; Infant, Extremely Premature; Infant, Newborn; Ligation
PubMed: 31740267
DOI: 10.1016/j.pedneo.2019.10.002 -
Journal of the American Heart... Sep 2022The burden of patent ductus arteriosus (PDA) continues to be significant. In view of marked differences in preterm infants versus more mature, term counterparts (viewed... (Review)
Review
The burden of patent ductus arteriosus (PDA) continues to be significant. In view of marked differences in preterm infants versus more mature, term counterparts (viewed on a continuum with adolescent and adult patients), mechanisms regulating ductal patency, genetic contributions, clinical consequences, and diagnostic and treatment thresholds are discussed separately, when appropriate. Among both preterm infants and older children and adults, a range of hemodynamic profiles highlighting the markedly variable consequences of the PDA are provided. In most contemporary settings, transcatheter closure is preferable over surgical ligation, but data on longer-term outcomes, particularly among preterm infants, are lacking. The present review provides recommendations to identify gaps in PDA diagnosis, management, and treatment on which subsequent research can be developed. Ultimately, the combination of refined diagnostic thresholds and expanded treatment options provides the best opportunities to address the burden of PDA. Although fundamental gaps remain unanswered, the present review provides pediatric and adult cardiac care providers with a contemporary framework in PDA care to support the practice of evidence-based medicine.
Topics: Adolescent; Child; Ductus Arteriosus, Patent; Hemodynamics; Humans; Infant; Infant, Newborn; Infant, Premature; Ligation
PubMed: 36056734
DOI: 10.1161/JAHA.122.025784 -
JAMA Mar 2018Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to... (Comparative Study)
Comparative Study Meta-Analysis Review
Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis.
IMPORTANCE
Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA.
OBJECTIVES
To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates.
DATA SOURCES AND STUDY SELECTION
The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA.
DATA EXTRACTION AND SYNTHESIS
Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses.
MAIN OUTCOMES AND MEASURES
Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage.
RESULTS
In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities.
CONCLUSIONS AND RELEVANCE
A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage.
TRIAL REGISTRATION
PROSPERO Identifier: CRD42015015797.
Topics: Acetaminophen; Administration, Intravenous; Administration, Oral; Bayes Theorem; Cerebral Hemorrhage; Ductus Arteriosus, Patent; Enterocolitis, Necrotizing; Hemodynamics; Humans; Ibuprofen; Indomethacin; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 29584842
DOI: 10.1001/jama.2018.1896 -
American Journal of Respiratory and... Apr 2023Extremely preterm infants with evolving bronchopulmonary dysplasia (BPD) are at risk for development of BPD-associated pulmonary hypertension (BPD-PH). A patent ductus...
Extremely preterm infants with evolving bronchopulmonary dysplasia (BPD) are at risk for development of BPD-associated pulmonary hypertension (BPD-PH). A patent ductus arteriosus (PDA) shunt may be a modifiable risk factor for BPD-PH development. To determine whether the presence and duration of ductus arteriosus patency differs between extremely preterm infants with and without BPD-PH. We conducted a retrospective case-control study among preterm infants of gestational age 22 weeks, 0 days, to 28 weeks, 6 days, who remained on respiratory support on postnatal day 28 at the University of Alabama at Birmingham from 2017 to 2020. Infants who were diagnosed with PH (cases) by echocardiography were compared with infants without PH (control subjects). Data from echocardiograms performed during the hospitalization after postnatal day 28 were included. Logistic regression adjusted for covariates that differed significantly between groups. A probit analysis related the duration of ductal patency to the development of BPD-PH. A total of 138 infants developed BPD alone, and 82 infants developed BPD-PH. After adjustment for differing covariates between groups, both PDA (adjusted odds ratio, 4.29; 95% confidence interval, 1.89-9.77) and moderate to large PDA (adjusted odds ratio, 4.15; 95% confidence interval, 1.78-9.64) remained significantly related to BPD-PH at discharge. By probit analysis, each additional month of PDA and hemodynamically significant PDA exposure was associated with an increased probability for the composite outcome of BPD-PH at discharge or death with coefficients of 0.40 ( < 0.001) and 0.45 ( < 0.001), respectively. In extremely preterm infants on respiratory support on postnatal day 28, both the presence of and a longer duration of ductus arteriosus patency were associated with the development of BPD-PH.
Topics: Infant; Infant, Newborn; Humans; Bronchopulmonary Dysplasia; Ductus Arteriosus, Patent; Retrospective Studies; Hypertension, Pulmonary; Case-Control Studies; Infant, Extremely Premature; Pulmonary Arterial Hypertension
PubMed: 36378949
DOI: 10.1164/rccm.202203-0570OC -
Pediatrics and Neonatology Feb 2021Hemodynamic compromise of the neonate can occur in various clinical situations, including but not limited to maladaptation during the early transitional period, sepsis,... (Review)
Review
Hemodynamic compromise of the neonate can occur in various clinical situations, including but not limited to maladaptation during the early transitional period, sepsis, congenital heart anomalies, hemodynamically significant patent ductus arteriosus, persistent pulmonary hypertension of the newborn, systemic inflammatory diseases such as necrotizing enterocolitis, and dehydration. Despite the handful of advances in neonatal care through ground-breaking clinical trials, the management of neonatal shock is often dependent on the bedside clinician's experience and training without the aid of high-level evidence. However, the recognition for the importance of comprehensive and serial hemodynamic assessment is growing. There is now a wealth of literature investigating the use of functional echocardiography, near-infrared spectroscopy, and noninvasive impedance-based cardiometry to complement common bedside hemodynamic measures such as blood pressure and heart rate measurement. In this review article, the pathophysiology of neonatal hemodynamic compromise is outlined, and concomitant best-evidence management for hemodynamic compromise in the neonate is proposed.
Topics: Ductus Arteriosus, Patent; Echocardiography; Hemodynamics; Humans; Hypotension; Infant, Newborn; Infant, Premature; Shock
PubMed: 33485823
DOI: 10.1016/j.pedneo.2020.12.007 -
Scientific Reports May 2021To evaluate national epidemiologic data on infants treated for patent ductus arteriosus (PDA) in Korea and analyze outcomes associated with different PDA treatments. We...
To evaluate national epidemiologic data on infants treated for patent ductus arteriosus (PDA) in Korea and analyze outcomes associated with different PDA treatments. We retrospectively evaluated data on 12,336 patients diagnosed with PDA (International Classification of Diseases-10 code: Q250) between 2015 and 2018 from the Health Insurance Review and Assessment database. Among them, 1623 patients underwent surgical ligation (code: O1671). We used birth certificate data from Statistics Korea to estimate the prevalence, diagnosis, and treatment of PDA. The prevalence of infants with PDA was 81 infants per 10,000 live births and 45.2% in very low birth weight (VLBW) infants, which increased from 2015 to 2018. PDA ligation was performed in 2571 infants and 22% VLBW infants. Medical treatment was administered to 4202 infants, which decreased significantly, especially in VLBW infants (62% to 53%). The proportion of treatment was as follows: conservative treatment (53.1%), intravenous ibuprofen (24.4%), surgery (20.4%), and oral ibuprofen (10.7%); that among 4854 VLBW infants was as follows: intravenous ibuprofen (46.3%), conservative treatment (33.2%), surgery (22.2%), and oral ibuprofen (14.2%). Surgical treatment had a significantly higher risk (odds ratio 1.36) of mortality than conservative treatment. Surgical and/or medical treatments were associated with a higher risk of morbidity. Recently, increased use of conservative management of PDA has contributed to improved neonatal outcomes in VLBW infants. Select patients may still benefit from surgical ligation following careful consideration.
Topics: Clinical Decision-Making; Combined Modality Therapy; Disease Management; Ductus Arteriosus, Patent; Humans; Infant, Newborn; Odds Ratio; Outcome Assessment, Health Care; Prevalence
PubMed: 34021202
DOI: 10.1038/s41598-021-89868-z -
European Journal of Pediatrics Mar 2021Our aim was to assess the efficacy and safety of intravenous (i.v.) paracetamol vs. i.v. ibuprofen for the treatment of hemodynamically significant patent ductus... (Randomized Controlled Trial)
Randomized Controlled Trial
Our aim was to assess the efficacy and safety of intravenous (i.v.) paracetamol vs. i.v. ibuprofen for the treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. This is a multicenter randomized controlled study. Infants with a gestational age of 25-31 weeks were randomized to receive i.v. paracetamol (15 mg/kg/6 h for 3 days) or i.v. ibuprofen (10-5-5 mg/kg/day). The primary outcome was the closure rate of hsPDA after the first treatment course with paracetamol or ibuprofen. Secondary outcomes included the constriction rate of hsPDA, the re-opening rate, and the need for surgical closure. Fifty-two and 49 infants received paracetamol or ibuprofen, respectively. Paracetamol was less effective in closing hsPDA than ibuprofen (52 vs. 78%; P = 0.026), but the constriction rate of the ductus was similar (81 vs. 90%; P = 0.202), as confirmed by logistic regression analysis. The re-opening rate, the need for surgical closure, and the occurrence of adverse effects were also similar.Conclusions: Intravenous paracetamol was less effective in closing hsPDA than ibuprofen, but due to a similar constriction effect, its use was associated with the same hsPDA outcome. These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.Trial registration: Clinicaltrials.gov : NCT02422966, Date of registration: 04/09/2015; EudraCT no: 2013-003883-30. What is Known: • The successful closure of patent ductus arteriosus with oral paracetamol has been recently reported in several preterm infants, but only one randomized controlled study investigated the efficacy of intravenous paracetamol. What is New: • Intravenous paracetamol is less effective in closing hsPDA than ibuprofen, but have a similar constriction effect. • These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.
Topics: Acetaminophen; Ductus Arteriosus, Patent; Gestational Age; Humans; Ibuprofen; Infant; Infant, Newborn; Infant, Premature
PubMed: 32888085
DOI: 10.1007/s00431-020-03780-8 -
The Journal of Pediatrics Feb 2019To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given.
STUDY DESIGN
A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial.
RESULTS
At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%).
CONCLUSIONS
In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT01958320.
Topics: Acetaminophen; Conservative Treatment; Continuous Positive Airway Pressure; Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Female; Gestational Age; Humans; Ibuprofen; Indomethacin; Infant, Extremely Premature; Infant, Newborn; Male; Prospective Studies; Single-Blind Method; Treatment Outcome
PubMed: 30340932
DOI: 10.1016/j.jpeds.2018.09.012 -
Clinics in Perinatology Mar 2022Percutaneous-based patent ductus arteriosus closure is technically feasible among infants less than 1.5 kg. However, marked heterogeneity in the type and nature of... (Review)
Review
Percutaneous-based patent ductus arteriosus closure is technically feasible among infants less than 1.5 kg. However, marked heterogeneity in the type and nature of adverse events obscures current safety profile assessments. Although data on the risks of postdevice closure syndrome remain promising, a lack of comparative trials of surgical ductal ligation and inconsistent surveillance across published studies obscure confidence in present estimates of safety and efficacy. To minimize risk and yield the greatest benefits, clinical studies of patent ductus arteriosus treatment should consider incorporating more robust assessments to ensure that infants at greatest risk for adverse ductal consequences are included.
Topics: Ductus Arteriosus, Patent; Humans; Infant; Infant, Newborn; Infant, Premature; Ligation; Treatment Outcome
PubMed: 35209997
DOI: 10.1016/j.clp.2021.11.009