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Objective An alternative therapy for preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) is needed when cyclooxygenase inhibitors fail or where treatment is contraindicated due to coexisting renal failure, necrotizing enterocolitis, and/or intestinal perforation. No studies have evaluated the efficacy of per rectum (PR) acetaminophen. The study aimed to evaluate the efficacy of PR acetaminophen in modulating the risk of PDA ligation. Study Design A retrospective matched case–control study was conducted to compare neonates born <29 weeks' gestation with evidence of hsDA, in an era when rescue rectal acetaminophen was used (January 2014–March 2018) as a treatment strategy, versus historical controls (July 2006–August 2012). All patients underwent comprehensive echocardiography assessment of ductal shunt volume according to a standardized protocol. Acetaminophen treated neonates were matched according to demographics, gestation, preintervention echocardiography features, and comorbidities. Control patients were selected when an echocardiography was performed at an equivalent postnatal age. Infants with a genetic syndrome, severe congenital malformation, or major forms of congenital heart disease excluding small atrial septal defect or ventricular septal defect, PDA, or patent formale ovale were excluded. The primary outcome was surgical ligation of the PDA. Secondary outcomes included echocardiography indices of hemodynamic significance, the composite of death, or severe BPD (defined by ventilator dependence at 36 weeks postmenstrual age). Descriptive statistics and univariate (t -tests, Fisher's exact test, and Mann–Whitney U test) analyses were used to evaluate clinical and echocardiography characteristics of the groups and compare outcomes. Results Forty infants (20 cases and 20 controls), with similar demographic and echocardiography features, were compared. Cases received 6.8 ± 0.7 days (60 mg/kg/day) of PR acetaminophen. Responders (n = 12, 60%) had echocardiography evidence of reduced ductal diameter (2.2 mm [1.9–2.6] to 1.1 mm [0–1.7], p = 0.002), left ventricular output (363 ± 108–249 ± 61 mL/min/kg; p = 0.002) and left atrium to aortic root ratio (1.7 ± 0.3–1.3 ± 0.2; p = 0.002) following treatment. The rate of PDA ligation was 50% lower (p = 0.02) and composite outcome of death or severe bronchopulmonary dysplasia was reduced (p = 0.04) in the acetaminophen group. Conclusion Rectal acetaminophen was associated with improvement in echocardiography indices of PDA shunt volume, a 50% reduction in PDA ligation rates and a reduction in the composite outcome of death or severe BPD. Pharmacologic and further prospective clinical studies are needed. Key Points Many preterm infants encounter the clinical consequences of a hemodynamically significant PDA. The merits and optimal timing of PDA ligation remains an area of controversy amongst neonatologists. Cyclooxygenase inhibitors are associated with adverse events or are often contraindicated. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the relationship of echocardiographic markers of left heart overload and flow in peripheral major end‐organ vessels (eg, celiac artery) with the presence of reversed holodiastolic flow in the descending aorta, considered a surrogate marker of an increased transductal shunt volume, in preterm patients with a patent ductus arteriosus (PDA). Methods: This work was a retrospective study of data from echocardiography performed to investigate the hemodynamic significance of a PDA in preterm patients. We studied differences in echocardiographic markers of the PDA shunt volume according to patterns of flow in the postductal descending aorta (no PDA, PDA with antegrade diastolic flow, and PDA with reversed diastolic flow). The strength of the association between each echocardiographic marker and the presence of aortic holodiastolic flow reversal was investigated. Results: We studied 137 patients with a median (interquartile range) birth weight of 850 (694–1030) g and a median gestational age of 25 (24–27) weeks. Among patients with a PDA (113), those with diastolic flow reversal in the descending aorta (44) presented had increased echocardiographic markers representative of the shunt volume (increased left ventricular output, left atrial‐to‐aortic ratio, pulmonary vein D wave, and shorter isovolumic relaxation time) compared to those with aortic antegrade diastolic flow. A positive, albeit weak, correlation between diastolic flow reversal and shunt volume echocardiographic markers was found. Abnormal diastolic flow in the celiac artery had the strongest correlation (R2 = 0.24). Conclusions: In preterm patients with a PDA, echocardiographic markers of the shunt volume were more abnormal in patients with reversed diastolic flow in the descending aorta. These data support the assumption that variance in these markers are related to the shunt volume, which needs consideration when adjudicating hemodynamic significance. [ABSTRACT FROM AUTHOR]

Aim: To investigate the relationship between changes in urine output during indomethacin treatment and ductal closure in preterm neonates.Methods: It is a retrospective study in neonates ≤32 weeks who had received two courses of indomethacin for PDA treatment over a 5-year period. Indomethacin courses with pre- and post-echocardiography confirmation of PDA status were included. Various urine output indices were collected and compared between successful versus unsuccessful indomethacin courses. Indomethacin treatment success was defined as: (i) where PDA closed or became haemodynamically insignificant (hisPDA) after treatment and (ii) only including neonates where PDA had complete closure after treatment. ROC analysis was performed to examine predictive ability of urine output during indomethacin for treatment success.Results: One hundred and eight indomethacin courses (first course: 52, second course: 56) in 80 neonates were included. The mean gestational age and birthweight were 25.4 ± 1.3 weeks and 762 ± 165 g, respectively. Irrespective of the definition used, there was no significant differences seen in any of urine output parameters between groups, except for a higher urine output during indomethacin associated with complete PDA closure (3.6 ± 1.3 vs. 3.0 ± 1.0 mL/kg/h, P = 0.02). The incidence of significant oliguria, hyponatraemia and need to withhold/delay indomethacin doses were also similar across groups.Conclusion: Urine output was not a useful predictor of ductal response to indomethacin treatment in preterm neonates. [ABSTRACT FROM AUTHOR]

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The transition from intrauterine to extrauterine life represents a critical phase of physiological adaptation which impacts many organ systems, most notably the heart and the lungs. The majority of term neonates complete this transition without complications; however, dysregulation of normal postnatal adaptation may lead to acute cardiopulmonary instability, necessitating advanced intensive care support. Although not as well appreciated as changes in vascular resistances, the shunt across the DA plays a crucial physiologic role in the adaptive processes related to normal transitional circulation. Further, we describe key differences in the behavior of the ductal shunt during transition in preterm neonates and we postulate mechanisms through which the DA may modulate major hemodynamic complications during this vulnerable period. Finally, we describe the conditions in which preservation of ductal patency is a desired clinical goal and we discuss clinical factors that may determine adequate balance between pulmonary and systemic circulation. [ABSTRACT FROM AUTHOR]

Background: Failure of first course of indomethacin (FCI) for patent ductus arteriosus (PDA) treatment in preterm neonates often prompts clinicians to consider a second course (SCI).Objective: To identify factors including baseline characteristics and response to FCI that are associated with non-response to SCI for PDA treatment in preterm neonates.Methods: In this retrospective observational study, neonates ≤32 weeks admitted to a tertiary NICU over 5 years who received two indomethacin courses for PDA treatment were reviewed. Only neonates with echocardiograms (ECHO) immediately before and after receipt of each indomethacin course were included. Primary outcome was non-response to SCI. Baseline characteristics and response to FCI were compared between responders and non-responders of SCI.Results: Of the 98 neonates enrolled, 47 (48%) had non-response to SCI. Of them, 27 patients (57%) had prior non-response to FCI, while of the 51 neonates who responded to SCI, 24 neonates (47%) had prior non-response to FCI. The adjusted risk of non-response to SCI in patients who had non-response to FCI was 37% higher (relative risk = 1.37, 95%CI: 0.87-1.80; p = .07) compared to those who had response to FCI. Multivariable analysis showed that increasing gestational age (AOR: 1.6, 95%CI: 1.1-2.3, p = .03) was associated with a higher odds of non-response to SCI while the odds of non-response to SCI increased by 90% in patients with non-response to FCI (AOR: 1.9, 95%CI: 0.8-4.5; p = .15) compared to those with success of FCI, although no statistical significance was observed.Conclusions: Advanced gestational age was the predictor of non-response to SCI in preterm neonates. [ABSTRACT FROM AUTHOR]

Introduction The postoperative course of preterm babies undergoing surgical closure of a patent ductus arteriosus (PDA) is often complicated by postligation cardiac syndrome (PLCS). Despite targeted milrinone prophylaxis, some infants continue to experience postoperative respiratory deterioration. Our objective is to describe the immediate postoperative course and identify risk factors for respiratory instability when preterm infants undergoing PDA ligation are managed with targeted milrinone treatment. Methods A retrospective review of a cohort of infants undergoing PDA ligation between January, 2010 and August, 2013 was conducted. All infants had a targeted neonatal echocardiogram performed 1 hour after surgery. Infants received prophylactic milrinone treatment if the left ventricular output was <200 mL/kg/min. The primary outcome measure was the development of respiratory instability within 24 hours of surgery. Multivariable logistic regression was performed to identify predictors of respiratory instability. Results Eighty-six infants with a median gestational age of 25 weeks (interquartile range [IQR], 24-26) and a birth weight of 740 g (IQR, 640-853) were included in this study. Forty-nine (57.0%) received milrinone prophylaxis. There were 44 (51.2%) infants who developed oxygenation or ventilation failure, and 7 (8.1%) neonates developed PLCS. Infants with longer isovolumic relaxation time (IVRT ≥30 milliseconds) were more likely to develop either oxygenation or ventilation failure. Conclusions Although the incidence of PLCS has declined after the introduction of targeted milrinone prophylaxis, many preterm infants continue to develop respiratory instability after surgical ligation. In this population, diastolic dysfunction manifested by prolonged IVRT could be associated with an adverse postoperative respiratory course. [ABSTRACT FROM AUTHOR]

Background: Non-invasive cardiac output monitoring (NICOM; NICOM™) may be useful in the management of extremely premature preterm infants. Objectives: To evaluate a new bioreactance-based method of continuous NICOM in preterm infants following patent ductus arteriosus (PDA) ligation. Methods: Infants underwent three paired NICOM and echocardiography assessments of stroke volume (SV) and left ventricular output (LVO) in the postoperative period: at 1, 6-8, and 16-18 h postoperatively. NICOM- and echocardiography-measured SV and LVO during those periods were compared using Bland-Altman analysis and the intraclass correlation coefficient (ICC). Results: Twenty-five infants with a median (interquartile range) gestational age and birth weight of 25.0 weeks (24.5-25.9) and 700 g (615-775), respectively, were included. The overall systematic bias (limits of agreement) across all time points between the NICOM and echocardiography SV readings was 39% (8-69) with NICOM consistently underestimating echocardiography values. There was moderate consistency between NICOM and echocardiography SV values (ICC 0.78, p < 0.001). Compared with the 1-hour scans, the 6- to 8- and 16- to 18-hour scans had increased biases of 7.9% (95% CI 2.5-13.2) and 9.7% (95% CI 3.6-15.8), respectively. Conclusion: Continuous LVO measurement using NICOM was feasible and demonstrated a consistent systematic bias compared with echocardiography in unstable extremely preterm infants without a PDA ligation. NICOM may be used as a trending tool for continuous monitoring in this population, but wide limits of agreement and increasing bias over time suggest it is not interchangeable with echocardiography. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Targeted milrinone treatment for low left ventricular output (LVO) reduces the incidence of acute cardiorespiratory instability following ligation of patent ductus arteriosus (PDA) in preterm infants. Despite this, some infants continue to experience postoperative deterioration. Adrenal insufficiency related to prematurity has been postulated as a possible mechanism. Objectives: To describe adrenal function in premature infants undergoing PDA ligation and to investigate its association with pre- and postoperative clinical and echocardiography-derived indices of disease severity. Methods: A retrospective cohort study was conducted over a 2-year period on infants who underwent PDA ligation and had preoperative adrenocorticotropic hormone (ACTH) stimulation. All infants were screened by echocardiography for low LVO at 1 h after surgery and treated with intravenous milrinone if LVO <200 ml/kg/min. The primary outcome evaluated was low LVO at 1 h after surgery. Secondary outcomes included hypotension and oxygenation and ventilation failure occurring within 24 h. Results: A total of 35 infants at a median gestation of 25.4 (24.5-26.4) weeks and weight at birth of 700 (600-810) g were included. Baseline median cortisol measured preoperatively was 202 (137-403) nmol/l. Following the ACTH stimulation test, 3 infants had cortisol ≤500 nmol/l while 15 had ≤750 nmol/l. There was no association seen between any cortisol value and low LVO postoperatively. Post-ACTH cortisol ≤750 nmol/l was significantly associated with hypotension (p = 0.03) and oxygenation (p = 0.04) and ventilation (p = 0.008) failure. Receiver-operator characteristic curve showed a high predictive value of post-ACTH cortisol for all clinical outcomes. Conclusions: Post-ACTH cortisol (≤750 nmol/l) may be associated with clinical indices of postoperative cardiorespiratory instability. Relative adrenal insufficiency may play a role in the etiology of post-PDA ligation hemodynamic and respiratory instability. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To investigate the circulatory physiology of hypotension during the first day after birth among stable extremely preterm neonates.Study Design: Case-control study of neonates born at ≤276/7 weeks gestational age with hypotension, defined as mean blood pressure in mmHg less than gestational age in weeks for at least 1 hour during the first 24 hours after birth, who underwent comprehensive echocardiography assessment before commencement of cardiovascular drugs. Neonates with hypotension (n = 14) were matched by gestational age and intensity of respiratory support with normotensive neonates (n = 27) who underwent serial echocardiography during the first day after birth, and relatively contemporaneous echocardiography assessments were used for comparison.Results: Neonates with hypotension had a higher frequency of patent ductus arteriosus ≥1.5 mm (71% vs 15%; P < .001) and ductal size (median diameter, 1.6 mm [IQR, 1.4-2.1] vs 1.0 mm [IQR, 0-1.3]; P = .002), higher echocardiography indices of left ventricular systolic function (mean shortening fraction, 34 ± 7% vs 26 ± 4%; P < .001; mean longitudinal strain, -16 ± 5% vs -14 ± 3%; P = .04; and mean velocity of circumferential fiber shortening, 1.24 ± 0.35 circ/s vs 1.01 ± 0.28 circ/s; P = .03), lower estimates of left ventricular afterload (mean end-systolic wall stress, 20 ± 7 g/cm2 vs 30 ± 9 g/cm2; P < .001 and mean arterial elastance, 43 ± 19 mmHg/mL vs 60 ± 22 mmHg/mL; P = .01), without significant difference in stress-velocity index z-score (-0.42 ± 1.60 vs -0.88 ± 1.30; P = .33). Neonates with hypotension had higher rates of any degree of intraventricular hemorrhage (71% vs 22%; P = .006).Conclusions: Low blood pressure in otherwise well extremely low gestational age neonates was associated with low systemic afterload and larger patent ductus arteriosus, but not left ventricular dysfunction. [ABSTRACT FROM AUTHOR]

Objectives: To assess associations between neonatal intensive care unit (NICU)-level patent ductus arteriosus (PDA) treatment rates (pharmacologic or surgical) and neonatal outcomes.Study Design: This cohort study included infants born at 24-28 weeks of gestation and birth weight <1500 g in 2007-2015 in NICUs caring for ≥100 eligible infants in 6 countries. The ratio of observed/expected (O/E) PDA treatment rates was derived for each NICU by estimating the expected rate using a logistic regression model adjusted for potential confounders and network. The primary composite outcome was death or severe neurologic injury (grades III-IV intraventricular hemorrhage or periventricular leukomalacia). The associations between the NICU-level O/E PDA treatment ratio and neonatal outcomes were assessed using linear regression analyses including a quadratic effect (a square term) of the O/E PDA treatment ratio.Results: From 139 NICUs, 39 096 infants were included. The overall PDA treatment rate was 45% in the cohort (13%-77% by NICU) and the O/E PDA treatment ratio ranged from 0.30 to 2.14. The relationship between the O/E PDA treatment ratio and primary composite outcome was U-shaped, with the nadir at a ratio of 1.13 and a significant quadratic effect (P<.001). U-shaped relationships were also identified with death, severe neurologic injury, and necrotizing enterocolitis.Conclusions: Both low and high PDA treatment rates were associated with death or severe neurologic injury, whereas a moderate approach was associated with optimal outcomes. [ABSTRACT FROM AUTHOR]