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BACKGROUND Our understanding of the normative concentrations of urine biomarkers in premature neonates is limited. METHODS We evaluated urine from 750 extremely low gestational age (GA) neonates without severe acute kidney injury (AKI) to determine how GA affects ten different urine biomarkers at birth and over the first 30 postnatal days. Then, we investigated if the urine biomarkers changed over time at 27, 30, and 34 weeks postmenstrual age (PMA). Next, we evaluated the impact of sex on urine biomarker concentrations at birth and over time. Finally, we evaluated if urine biomarkers were impacted by treatment with erythropoietin (Epo). RESULTS We found that all ten biomarker concentrations differ at birth by GA and that some urine biomarker concentrations increase, while others decrease over time. At 27 weeks PMA, 7/10 urine biomarkers differed by GA. By 30 weeks PMA, 5/10 differed, and by 34 weeks PMA, only osteopontin differed by GA. About half of the biomarker concentrations differed by sex, and 4/10 showed different rates of change over time between males vs. females. We found no differences in urine biomarkers by treatment group. CONCLUSIONS The temporal patterns, GA, and sex differences need to be considered in urine AKI biomarker analyses. IMPACT Urine biomarker concentrations differ by GA at birth. Some urine biomarkers increase, while others decrease, over the first 30 postnatal days. Most urine biomarkers differ by GA at 27 weeks PMA, but are similar by 34 weeks PMA. Some urine biomarkers vary by sex in premature neonates. Urine biomarkers did not differ between neonates randomized to placebo vs. Epo.

Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure.To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions.The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019.In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks.Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein.A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P .001).These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants.ClinicalTrials.gov Identifier: NCT01378273.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.)

Objective To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). Study design Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). Results Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. Conclusion Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. Trial registration ClinicalTrials.gov : NCT01022580

ObjectiveTo assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD).Study designExtremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction.ResultsA total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA

Objective To quantify intercenter cost variation for perinatal hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia across children's hospitals. Study design Prospectively collected data from the Children's Hospitals Neonatal Database and Pediatric Health Information Systems were linked to evaluate intercenter cost variation in total hospitalization costs after adjusting for HIE severity, mortality, length of stay, use of extracorporeal support or nitric oxide, and ventilator days. Secondarily, costs for intensive care unit bed, electroencephalography (EEG), and laboratory and neuroimaging testing were also evaluated. Costs were contextualized by frequency of favorable (survival with normal magnetic resonance imaging) and adverse (death or need for gastric tube feedings at discharge) outcomes to identify centers with relative low costs and favorable outcomes. Results Of the 822 infants with HIE treated with therapeutic hypothermia at 19 regional neonatal intensive care units, 704 (86%) survived to discharge. The median cost/case for survivors was $58 552 (IQR $32 476-$130 203) and nonsurvivors $29 760 (IQR $16 897-$61 399). Adjusting for illness severity and select interventions, intercenter differences explained 29% of the variation in total hospitalization costs. The widest cost variability across centers was EEG use, although low cost and favorable outcome centers ranked higher with regards to EEG costs. Conclusions There is marked intercenter cost variation associated with treating HIE across regional children's hospitals. Our investigation may help establish references for cost and enhance quality improvement and resource utilization projects related to HIE.

Objective To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship. Study design We assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis. Results Of 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively. Conclusions Among former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences. Trial registration ClinicalTrials.gov : NCT01022580 .

The aim of this study was to identify independent predictors of acquiring a nosocomial bloodstream infection (BSI) during extracorporeal membrane oxygenation (ECMO).This retrospective cohort consisted of 202 neonates treated with ECMO from 1989 to 1998 at the author' institution. Data collected included patient demographics, primary and secondary diagnoses, white blood cell counts, antibiotic usage, presence of central lines, operative procedures, and outcome. Surveillance blood cultures were drawn daily from the circuit using sterile technique to identify acquired pathogens. Statistical analyses included logistic regression, Cox proportional regression analysis, and discriminate analysis.There were 1,245 blood cultures drawn on 202 patients (6.2 cultures per patient), and a nosocomial BSI was identified in 7 patients (3.4%) during this 10-year span. These were infections that were neither present nor incubating on admission. Pre-ECMO diagnoses of patients who had a nosocomial BSI while on bypass included group B beta-hemolytic streptococcal sepsis (n = 2), herpes simplex viral sepsis (n = 1), congenital diaphragmatic hernia (n = 2), persistent pulmonary hypertension (n = 1), and congenital heart disease (n = 1). The median time on ECMO before obtaining a positive culture was 390 hours. The infectious agents responsible for these BSIs included Staphylococcus epidermidis (n = 5), Staphylococcus aureus (n = 1), and Escherichia coli (n = 1). The major factor associated with acquiring a nosocomial BSI on ECMO was the duration of bypass (391 v 141 hours, P =.002). Additionally, patients in the BSI group were more likely to have had an arterial catheter in place (16 v 7 days, P =.009) and to have received more screening blood cultures (16 v 6 cultures, P001). White blood cell counts, absolute neutrophil counts, and immature/total (I/T) ratios were not useful in predicting a nosocomial BSI. Of the 31 patients who required ECMO for more than 10 days, 7 (23%) had a positive blood culture, and 5 of these 7 infants (71%) died (P =.03).The only predictor of acquiring a nosocomial BSI on ECMO was the duration of support for greater than 10 days. Because classical predictors of infection are unreliable while the patient is on ECMO, the authors suggest that obtaining daily surveillance blood cultures beginning on the tenth day should be performed with prolonged ECMO courses. The authors confirmed previous reports of the association between a prolonged ECMO course and a high mortality rate. However, the authors speculate that, in actuality, the primary diagnosis leads to the prolonged course of support and is the major factor in the infant' demise.

The retention of extracorporeal membrane oxygenation (ECMO) cannulae of ECMO is discontinued was originally developed to avoid reexploration of the neck in patients who may require a second course of ECMO. Because of the incidence, at the authors' institution, of thrombi noted on the ends of retained cannulae and their potential to cause significant morbidity, a critical review of this procedure was initiated. A telephone survey of 72 Extracorporeal Life Support Organization (ELSO) centers was conducted, and ELSO registry forms were requested for patients who had their cannulae retained. Twenty-four of these centers had performed the procedure of retaining ECMO cannulae. There were 324 neonatal and pediatric patients who had their cannulae retained, with 41 patients (12%) requiring a second course of ECMO and 17 of 41 (41%) surviving the second course. Twelve of the 24 ELSO centers that retain cannulae have reported complications. Analyses of the patients who had their cannulae retained showed that the three best predictors for requiring a second course of ECMO were the diagnosis of congenital diaphragmatic hernia (CDH) a high oxygenation index just before the initiation of ECMO, and a lengthy first ECMO course. The only difference between the survivors and nonsurvivors of the second course of ECMO was the length of the first ECMO course (P < .05). Five of the 25 patients who required two courses of ECMO had serious complications from their retained cannulae and all were nonsurvivors. The authors conclude that patients with retained ECMO cannulae are at high risk for developing thrombi, which can lead to severe embolic events. Therefore, the procedure of retaining cannulae should only be used in patients at high risk for requiring a second course of ECMO and not for the convenience of surgical availability to remove the cannulae.

The aim of this study is to document our experience with the use of extracorporeal life support (ECLS) in the neonatal cardiac patient, to detect differences in the morbidity and mortality between patients who required ECLS preoperatively and those who required ECLS postoperatively, and to determine the long-term effects of these morbidities.A chart review was undertaken of all neonatal cardiac patients who required ECLS between May 1985 and July 1994 at Kosair Children’s Hospital, Louisville, Kentucky.Twenty-three neonatal cardiac patients had received preoperative or postoperative ECLS with an overall survival rate of 35%. Our preoperative and postoperative patients had similar demographics, diagnoses, decannulation rates and survival rates. However, patients receiving postoperative ECLS more frequently required more than two inotropes ( p < 0.001), had an increased incidence of renal failure ( p < 0.02), had more central nervous system abnormalities on brain imaging studies ( p < 0.004), and had a longer hospital stay ( p < 0.05). Follow-up testing of survivors yielded normal Bayley Scale of Infant Development (BSID) scores in half of the patients.Survival in the two groups was similar, but a significant difference in morbidity was found. Except for severe intracranial abnormalities, the morbidity was shown to be reversible on follow-up examination. We recommend the continued use of ECLS for neonatal cardiac patients who require preoperative or postoperative support even when severe renal failure ensues or minor abnormalities are detected on brain imaging studies.