Dany E. Weisz

Association of Patent Ductus Arteriosus Ligation With Death or Neurodevelopmental Impairment Among Extremely Preterm Infants

Importance Observational studies have associated patent ductus arteriosus (PDA) ligation among preterm infants with adverse neonatal outcomes and neurodevelopmental impairment in early childhood, with a resultant secular trend away from surgical treatment. However, to our knowledge, studies have inadequately addressed sources of residual bias, including survival bias and major neonatal morbidities arising before exposure to ligation. Objective Evaluate the association between PDA ligation vs medical management and neonatal and neurodevelopmental outcomes. Design, Setting, and Participants This retrospective cohort study of preterm infants younger than 28 weeks gestational age born between January 1, 2006, and December 31, 2012, with clinical and echocardiography diagnoses of hemodynamically significant PDA was conducted at 3 tertiary neonatal intensive care units and affiliated follow-up programs. Exposure Surgical ligation vs medical management. Main Outcomes and Measures The primary outcome was a composite of death or neurodevelopmental impairment (NDI) at 18 to 24 months corrected age. Secondary outcomes included death before discharge, NDI, moderate-severe chronic lung disease, and severe retinopathy of prematurity. Multivariable logistic regression analysis was used to adjust for perinatal and postnatal confounders. Results Of 754 infants with hemodynamically significant PDA (mean [standard deviation] gestational age 25.7 [1.2] weeks and birth weight 813 [183] grams), 184 (24%) underwent ligation. Infants who underwent ligation had a higher frequency of morbidities before PDA closure, including sepsis, necrotizing enterocolitis, and a dependence on mechanical ventilation. After adjusting for perinatal characteristics and preligation morbidities, there was no difference in the odds of death or NDI (adjusted odds ratio (aOR), 0.83; 95% CI, 0.52-1.32), NDI (aOR, 1.27; 95% CI, 0.78-2.06), chronic lung disease (aOR, 1.36; 95% CI, 0.78-2.39) or severe retinopathy of prematurity (aOR, 1.61; 95% CI, 0.85-3.06). Ligation was associated with lower odds of mortality (aOR, 0.09; 95% CI, 0.04-0.21). Conclusions and Relevance Patent ductus arteriosus ligation among preterm neonates younger than 28 weeks gestational age was not associated with the composite outcome of death or NDI, and there were no differences in chronic lung disease, retinopathy of prematurity, or NDI among survivors. Mortality was lower among infants who underwent ligation, though residual survival bias could not be excluded. Previously reported associations of ligation with increased morbidity may be because of bias from confounding by indication.

Reflections of the changes in patent ductus arteriosus management during the last 10 years

Despite a large body of scientific evidence on the management of premature infants with a patent ductus arteriosus controversy remains and neonatologists remain challenged for knowing which patient to treat, what is the most optimal timing of treatment and which treatments have a positive impact on both short-term and long-term outcomes. In this review article we discuss the increased body of evidence over the past 10 years, much of which questions the role of treatment and suggests the need to reconsider how haemodynamic significance is adjudicated. In addition, we discuss novel approaches to assessment and diagnosis, and highlight areas for future investigation.

Acetaminophen to avoid surgical ligation in extremely low gestational age neonates with persistent hemodynamically significant patent ductus arteriosus

Objective:The objective of this study was to evaluate the effectiveness of rescue oral acetaminophen in improving echocardiography (echo) indices of patent ductus arteriosus (PDA) shunt volume and avoiding surgical ligation in extremely low gestational age (GA) neonates (ELGANs, <28 weeks) with persistent PDA.Study Design:Retrospective cohort study of ELGANs with moderate or severe PDA at risk for ligation after a practice change introducing oral acetaminophen (60 mg kg−1 day−1 for 3 to 7 days) to facilitate ductal constriction after indomethacin failure.Results:Twenty-six infants (median GA 24.4 weeks at birth) with persistent PDA under consideration for surgical ligation were treated with oral acetaminophen at a mean of 27 days of life. Echo indices of shunt volume improved in 12 (46%) infants (3 closed and 9 reduced to mild shunt), all of whom avoided ligation. There was no echo improvement in 14 (54%) infants, of which 8/14 underwent ligation, and ligation was deferred in 6/14 infants, mostly owing to improvement in respiratory stability. Fewer responders than non-responders underwent ligation (0% vs 57%, P<0.01), though there were no differences in other neonatal outcomes.Conclusions:In ELGANs with persistent significant PDA, rescue therapy with oral acetaminophen was associated with improvement in echo indices of shunt volume and avoidance of ligation in nearly half of infants.

Cardiac biomarkers and haemodynamically significant patent ductus arteriosus in preterm infants.

Accurately defining haemodynamically significant patent ductus arteriosus (PDA) in preterm infants who are at risk of PDA related morbidities are active areas of neonatal research. Natriuretic peptides are cardiac hormones that respond to volume and pressure loading, with elevated plasma levels found in infants with PDA. In the preterm neonatal setting, studies to date have predominantly investigated the ability of these biomarkers to discriminate between infants with and without a PDA at various postnatal ages. Their clinical utility has therefore been exclusively evaluated as a method of triaging cases of suspected hsPDA to decrease the need for echocardiograms, and to monitor treatment response. Biomarkers are yet to be robustly investigated for their ability to predict important PDA associated morbidities. In this review, we examine the most recent literature to date on the use of biomarkers in the management of PDA.

Outcomes of Surgical Ligation after Unsuccessful Pharmacotherapy for Patent Ductus Arteriosus in Neonates Born Extremely Preterm

&NA; A retrospective cohort study of neonates born extremely preterm with persistent patent ductus arteriosus after unsuccessful pharmacologic closure compared outcomes between 166 surgically ligated and 142 nonligated neonates. After adjustment for confounders, ligation was not associated with the composite outcome of death or neurodevelopmental impairment, neurodevelopmental impairment alone, chronic lung disease, or retinopathy of prematurity among survivors.

Late oral acetaminophen versus immediate surgical ligation in preterm infants with persistent large patent ductus arteriosus

Objective The study objective was to evaluate the association of oral acetaminophen therapy versus immediate surgical ligation with neonatal outcomes in infants with persistent patent ductus arteriosus. Methods We performed a retrospective cohort study of preterm infants born 28+6 weeks or less gestational age with persistent large patent ductus arteriosus being considered for surgical ligation after unsuccessful medical therapy. Infants in epoch 1 (July 2009 to June 2012) were immediately referred for ligation, and infants in epoch 2 (July 2012 to June 2015) were treated with oral acetaminophen and referred for ligation in the absence of improvement. The primary outcome was a composite of death or chronic lung disease. Results A total of 92 infants with median (interquartile range) gestational age 25.2 weeks (24.4‐26.3) had persistent large patent ductus arteriosus (43 in epoch 1, 49 in epoch 2). Infants in epoch 2 had decreased surgical ligation (26 [53%] vs 31 [72%]; adjusted odds ratio [aOR], 0.32; 95% confidence interval [CI], 0.12‐0.89) but increased chronic lung disease (36 [73%] vs 25 [58%]; aOR, 3.34; 95% CI, 1.05‐10.58) and increased death/chronic lung disease of borderline significance (39 [80%] vs 29 [67%]; aOR, 3.09; 95% CI, 0.99‐9.63). Infants in epoch 2 took longer to wean off of positive pressure ventilation (28.5 vs 24 days after enrollment; aOR, 0.52; 95% CI, 0.31‐0.85). Conclusions Late oral acetaminophen therapy for infants with persistent patent ductus arteriosus is associated with reduced surgical ligation but increased chronic lung disease. In light of a lack of improvement in clinical outcomes, the individual contributory effects of acetaminophen, surgical ligation, and prolonged exposure to patent ductus arteriosus require further study to define the optimal approach.

Surgical management of a patent ductus arteriosus: Is this still an option?

The evolution of neonatal intensive care over the past decade has seen the role of surgical patent ductus arteriosus (PDA) ligation in preterm infants both decrease in scope and become laden with uncertainty. Associations of ligation with adverse neonatal and neurodevelopmental outcomes have rendered the ligation decision more challenging for clinicians and have been associated with a decline in surgical treatment, but these findings may be due to bias from confounding by indication in observational studies rather than a causal detrimental effect of ligation. Accordingly, ligation may still be indicated for infants with large ductal shunts and moderate-severe respiratory insufficiency in whom the prospect of timely spontaneous closure appears low. Ultimately a randomized trial of surgical ligation versus conservative management is necessary to assess the efficacy of this invasive intervention in a population of extremely preterm infants with large ductal shunts. Simultaneously, the transcatheter approach to ductal closure in the very immature infant represents an exciting therapeutic alternative but which is still in its infancy. Insights into the pathophysiology of postoperative cardiorespiratory deterioration, including the importance of left ventricular afterload, may help clinicians avoid instability and mitigate a potentially injurious aspect of surgical treatment. This review examines the evidence regarding the benefits and risks of PDA surgery in preterm neonates and provides a pathophysiology-based management paradigm to guide perioperative care in high-risk infants.

Outcomes of hypoxic respiratory failure at birth associated with previable rupture of membranes

Objective:To characterize clinical outcomes of infants born after previable rupture of membranes (pROM, < 23 weeks gestation and latency period ≥ 2 weeks) in relation to refractory hypoxic respiratory failure (rHRF).Study Design:pROM neonates categorized as rHRF (FiO2 > 0.6 for ≥ 2 h) and treated (high frequency ventilation + inhaled nitric oxide) were compared with no rHRF group. Primary outcome was survival until discharge. Factors associated with rHRF and mortality were identified.Result:Overall, mortality and disability rates were 28% and 22%, respectively. Treated rHRF group (n = 32) had longer period of ROM, mortality was (31% vs. 14%; p = 0.20), with similar survival-without-disability (54% vs. 47%; p = 0.67). Higher gestational age at birth [1.57 (1.03,2.39)] and cesarean delivery [12.6 (1.22,125)] were associated with increased survival.Conclusion:Birth after pROM is associated with high rates of adverse outcomes, independent of latency period. Following treatment, rHRF infants may have similar long-term outcomes as those without rHRF.

Merits and Perils of Targeted Neonatal Echocardiography-Based Hemodynamic Research: A Position Statement

In the neonatal setting, point-of-care ultrasound is increasingly being used to help clinicians with the evaluation of heart function. Practices in neonatology, particularly with regard to acute and chronic hemodynamic managements, were traditionally more driven on dogma and predefined thresholds and not always supported by demonstrable physiology. For the first time, targeted neonatal echocardiography (TNE) provided neonatal intensivists with a bedside tool that made real-time assessment of neonatal hemodynamics status feasible in even the tiniest of babies. This opened the door towards more targeted physiological driven practices, allowing us to test historical approaches to clinical problems in a more precise way. Despite the standardization of TNE training and the creation of a formalized curriculum, little attention has been paid to the establishment of an empirical framework to adjudicate scientific investigation. In this position statement, we reflect on the evolution of TNE in Canadian neonatal intensive care units, appraise its strengths and limitations, and suggest guiding principles for clinicians and researchers to consider as they take this field forward.