Automated Microfluidic System with Active Mixing Enables Rapid Analysis of Biomarkers in 5 µL of Whole Blood.

We developed a microfluidic device for the rapid analysis of biomarkers in small volumes of whole blood. This device includes an onboard plasma separation module connected to a downstream bioanalysis module in which plasma mixes with reagents and the results of a colorimetric assay are recorded. Actuation of onboard microvalves within a bioanalysis module creates active mixing conditions that allowed us to achieve solution homogeneity within 5 min. To demonstrate utility, we carried out glucose detection in our device. With 5 µL of whole blood as an input, our microfluidic device enabled a time-to-answer of 10 min with a limit of detection of 0.21 ± 0.04 mM for glucose. This device has immediate applications for rapid and sensitive monitoring of hypoglycemia at the point of care (POC). Furthermore, our automated microfluidic device represents a platform technology that may be used to detect other biomarkers in whole blood.

Necrotizing Enterocolitis in Very Low Birth Weight Neonates: A Natural History Study.

OBJECTIVE: We characterize the most recent natural history of necrotizing enterocolitis (NEC), as this is an essential first step in guiding the prevention and treatment of this disease in the present day. STUDY DESIGN: We performed a retrospective cohort study of neonates who were born at 23 to 29 weeks' gestation and birth weight <1,500 g who received care from the Pediatrix Medical Group between 2004 and 2019. We assessed the incidence of medical and surgical NEC and the patterns of initial antibiotic treatment to develop a contemporary cohort for further analysis. Among patients discharged between 2015 and 2019, we characterized the stage-specific risk factors for patients diagnosed with medical or surgical NEC, as well as patterns of disease onset, progression, biomarkers, and outcomes. We used the same approach to characterize patients diagnosed with suspected NEC. RESULTS: Among 34,032 patients in the contemporary cohort, 1,150 (3.4%) were diagnosed with medical NEC and 543 (1.6%) were diagnosed with surgical NEC. The temporal pattern of disease onset was different for medical and surgical NEC, with gestational age- and birth weight-specific risk disparities emerging earlier in surgical NEC. Thirty-day mortality was much greater among surgical NEC patients (medical NEC 16.4% vs. surgical NEC 43.0%), as were rates of various in-hospital and long-term outcomes. Suspected NEC was diagnosed in 1,256 (3.7%) patients, among whom risk factors and disease onset, progression, and outcomes closely resembled those of medical NEC. CONCLUSION: Analyzing data from a contemporary cohort enabled us to characterize the current, stage-specific natural history of NEC, including novel insights into suspected NEC. Future studies could leverage this cohort to characterize how specific patient characteristics, care processes, or biomarkers may influence or predict disease outcomes. KEY POINTS: · The incidence of NEC has reached a stable baseline in recent years.. · Risk factors for NEC vary in a stage-specific manner.. · The stage-specific onset and progression of NEC differ by gestational age and birth weight..

Prolonged Tracheal Intubation and the Association Between Patent Ductus Arteriosus and Bronchopulmonary Dysplasia: A Secondary Analysis of the PDA-TOLERATE trial.

In the PDA-TOLERATE trial, persistent (even for several weeks) moderate to large patent ductus arteriosus (PDA) was not associated with an increased risk of BPD when the infant required <10 days of intubation. However, in infants requiring intubation for ≥10 days, prolonged PDA exposure (≥11 days) was associated with an increased risk of moderate/severe BPD.

Universal Electrocardiographic Screening for Long QT Syndrome in Hospitalized Neonates.

OBJECTIVE: Long QT syndrome (LQTS) is a known cause of unexpected death, leading some to recommend routine neonatal electrocardiographic (ECG) screening. We used continuous electronic heart rate corrected QT interval (QTc) monitoring to screen for interval prolongation in a cohort of hospitalized neonates to identify those at a risk of having LQTS. We hypothesized that this screening method would yield an acceptable positive predictive value (PPV). STUDY DESIGN: A cohort of 589 infants hospitalized in a level II neonatal intensive care unit were screened through continuous electronic QTc monitoring linked to an investigator-designed, computerized data sniffer. Screening was conducted from days-of-life 3 through 7 or until hospital discharge. The data sniffer alerted investigators for a 24-hour average QTc of ≥475 ms. Positively screened patients were further evaluated with 12-lead ECG. RESULTS: Positive screens were obtained in 5.6% of patients, all of whom had negative follow-up ECG testing (PPV = 0%). Furthermore, one-quarter of positively screened neonates underwent echocardiography based on ECG findings, none of which identified clinically relevant pathology. CONCLUSION: Electronic monitoring of QTc in hospitalized neonates during the first week of life was not an efficient way to identify those at a risk of having LQTS. Conversely, screening triggered unnecessary testing.

Lack of Equipoise in the PDA-TOLERATE Trial: A Comparison of Eligible Infants Enrolled in the Trial and Those Treated Outside the Trial.

The PDA: TO LEave it alone or Respond And Treat Early trial compared the effects of 2 strategies for treatment of patent ductus arteriosus (PDA) in infants <280/7 weeks of gestation; however 137 potentially eligible infants were not recruited and received treatment of their PDA outside the PDA-TOLERATE trial due to "lack-of-physician-equipoise" (LPE). Despite being less mature and needing more respiratory support, infants with LPE had lower rates of mortality than enrolled infants. Infants with LPE treated before day 6 had lower rates of late respiratory morbidity than infants with LPE treated ≥day 6. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320.

PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age.

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.

Birth Size and Gestational Age Specific Outcomes of Inhaled Nitric Oxide Therapy in Preterm Neonates with Clinically Diagnosed Pulmonary Hypertension.

OBJECTIVE: Among neonates of 22 to 29 weeks' gestational age (GA) who required mechanical ventilation for the treatment of respiratory distress syndrome (RDS) and clinically diagnosed pulmonary hypertension (PH), we tested our hypothesis that the association between early treatment with inhaled nitric oxide (iNO) and survival would vary according to birth size and GA. STUDY DESIGN: Because iNO was not randomly prescribed to patients in this cohort, we used propensity score matching to pair a neonate who received iNO at a chronological age of ≤7 days with an unexposed neonate with similar baseline characteristics. The primary outcome was inhospital mortality, which we evaluated based on size for GA and GA strata using the Cox proportional hazards regression model. RESULTS: Among 1,531 neonates who met study criteria, we created a propensity score matched cohort of 615 pairs of neonates (iNO-exposed and unexposed). The risk of inhospital mortality for iNO-exposed neonates was observed only in the minority (<10%) who were large for GA, though this finding did not persist when matching for illness severity. CONCLUSION: Early treatment with iNO is not associated with survival in most extremely premature neonates with RDS and clinically diagnosed PH when stratified for birth size or GA.

Congenital diaphragmatic hernia: outcomes of neonates treated at Mayo Clinic with and without extracorporeal membrane oxygenation.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare anomaly with high mortality and long-term comorbid conditions. AIMS: Our aim was to describe the presenting characteristics, treatment, and outcomes of consecutive patients with CDH treated at our institution. METHODS: We performed a retrospective cohort study and identified consecutive neonates treated for CDH from 2001 to 2015 at our institution. For all patients identified, we reviewed hospital and postdischarge data for neonatal, disease, and treatment characteristics. We determined hospital survival overall and also according to the presence of prenatal diagnosis, liver herniation into the chest (liver up), and the use of extracorporeal membrane oxygenation (ECMO) in addition to surgery. We evaluated postdischarge chronic conditions in patients with at least one year of follow-up. RESULTS: Thirty-eight neonates were admitted for treatment during the study period. In three who were in extremis, life support was withdrawn. The other 35 underwent surgical repair, of whom eight received ECMO. The overall survival was 79% (30/38). Survival for those who had surgical correction of CDH but did not need ECMO was 89% (24/27); it was 75% (6/8) for those who received ECMO and had surgery. Hospital survival was lower for liver-up vs liver-down CDH (61% [11/18] vs 95% [19/20]; odds ratio, 0.08; 95% CI, 0.01-0.77; P = 0.01). Among survivors, the median duration of hospitalization was 31 (interquartile range, 20-73) days. Major chronic pulmonary and gastrointestinal disorders, failure to thrive, and neurodevelopmental delays were the most noted comorbid conditions after discharge, and all were more prevalent in those who required ECMO. CONCLUSION: The overall survival of neonates with CDH was 79%. Intrathoracic liver herniation was associated with more frequent use of ECMO and greater mortality. A substantial number of survivors, especially those who required ECMO, experienced chronic conditions after discharge.

What accounts for the association between late preterm births and risk of asthma?

BACKGROUND: Although results of many studies have indicated an increased risk of asthma in former late preterm (LPT) infants, most of these studies did not fully address covariate imbalance. OBJECTIVE: To compare the cumulative frequency of asthma in a population-based cohort of former LPT infants to that of matched term infants in their early childhood, when accounting for covariate imbalance. METHODS: From a population-based birth cohort of children born 2002-2006 in Olmsted County, Minnesota, we assessed a random sample of LPT (34 to 36 6/7 weeks) and frequency-matched term (37 to 40 6/7 weeks) infants. The subjects were followed-up through 2010 or censored based on the last date of contact, with the asthma status based on predetermined criteria. The Kaplan-Meier method was used to estimate the cumulative incidence of asthma during the study period. Cox models were used to estimate the hazard ratio and 95% confidence interval for the risk of asthma, when adjusting for potential confounders. RESULTS: LPT infants (n = 282) had a higher cumulative frequency of asthma than did term infants (n = 297), 29.9 versus 19.5%, respectively; p = 0.01. After adjusting for covariates associated with the risk of asthma, an LPT birth was not associated with a risk of asthma, whereas maternal smoking during pregnancy was associated with a risk of asthma. CONCLUSION: LPT birth was not independently associated with a risk of asthma and other atopic conditions. Clinicians should make an effort to reduce exposure to smoking during pregnancy as a modifiable risk factor for asthma.

Outcomes of a Quality Improvement Initiative to Prevent Unnecessary Packed Red Blood Cell Transfusions Among Extremely Low Birth-Weight Neonates.

BACKGROUND: Extremely low birth-weight (ELBW) infants frequently receive packed red blood cell (PRBC) transfusions. Recent studies have shown that more restrictive PRBC transfusion guidelines limit donor exposure and reduce transfusion-related costs without any increase in adverse clinical outcomes. PURPOSE: We developed and implemented an evidence-based PRBC transfusion guideline for ELBW infants treated in our unit and then measured provider adherence to this guideline. METHODS/SEARCH STRATEGY: We performed a retrospective review of all PRBC transfusions given to ELBW infants in 2012 (preguideline) and the first half of 2014 (postguideline). We identified the indication for each transfusion by reviewing physiological/laboratory data and the daily clinical note. We then determine whether each transfusion met criteria according to our new evidence-based guideline. FINDINGS/RESULTS: When extrapolating the newly developed protocol to 2012 data, less than 15% of transfusions among ELBW infants would have met the current evidence-based standard. Conversely, during the first 6 months of 2014, 61% of transfusions were administered in adherence to the guideline (P < 001). Using current cost estimates, this represents a projected cost savings of $31,000 in that 6-month period. IMPLICATIONS FOR PRACTICE: A multidisciplinary approach to improving PRBC transfusion practices results in potentially safer, more cost-effective care for ELBW infants. IMPLICATIONS FOR RESEARCH: Given the frequency, potential harms, and costs associated with PRBC transfusions in ELBW infants, it seems both feasible and important to pursue prospective clinical trials comparing permissive and restrictive approaches to transfusion in this vulnerable population.

Hyperoxia-induced changes in estradiol metabolism in postnatal airway smooth muscle.

Supplemental oxygen, used to treat hypoxia in preterm and term neonates, increases the risk of neonatal lung diseases, such as bronchopulmonary dysplasia (BPD) and asthma. There is a known sex predilection for BPD, but the underlying mechanisms are not clear. We tested the hypothesis that altered, local estradiol following hyperoxia contributes to pathophysiological changes observed in immature lung. In human fetal airway smooth muscle (fASM) cells exposed to normoxia or hyperoxia, we measured the expression of proteins involved in estrogen metabolism and cell proliferation responses to estradiol. In fASM cells, CYP1a1 expression was increased by hyperoxia, whereas hyperoxia-induced enhancement of cell proliferation was blunted by estradiol. Pharmacological studies indicated that these effects were attributable to upregulation of CYP1a1 and subsequent increased metabolism of estradiol to a downstream intermediate 2-methoxyestradiol. Microarray analysis of mouse lung exposed to 14 days of hyperoxia showed the most significant alteration in CYP1a1 expression, with minimal changes in expression of five other genes related to estrogen receptors, synthesis, and metabolism. Our novel results on estradiol metabolism in fetal and early postnatal lung in the context of hyperoxia indicate CYP1a1 as a potential mechanism for the protective effect of estradiol in hyperoxia-exposed immature lung, which may help explain the sex difference in neonatal lung diseases.

Polysialic acid as an antigen for monoclonal antibody HIgM12 to treat multiple sclerosis and other neurodegenerative disorders.

CNS regeneration is a desirable goal for diseases of brain and spinal cord. Current therapeutic strategies for the treatment of multiple sclerosis (MS) aim to eliminate detrimental effects of the immune system, so far without reversing disability or affecting long-term prognosis in patients. Approachable molecular targets that stimulate CNS repair are not part of the clinical praxis or have not been identified yet. The purpose of this study was to identify the molecular target of the human monoclonal antibody HIgM12. HIgM12 reverses motor deficits in chronically demyelinated mice, a model of MS. Here, we identified polysialic acid (PSA) attached to the neural cell adhesion molecule (NCAM) as the antigen for HIgM12 by using different NCAM knockout strains and through PSA removal from the NCAM protein core. Antibody binding to CNS tissue and primary cells, antibody-mediated cell adhesion, and neurite outgrowth on HIgM12-coated nitrocellulose was detected only in the presence of PSA as assessed by western blotting, immunoprecipitation, immunocytochemistry, and histochemistry. We conclude that HIgM12 mediates its in vivo and in vitro effects through binding to PSA and has the potential to be an effective therapy for MS and neurodegenerative diseases. The human antibody HIgM12 stimulates neurite outgrowth in vitro and promotes function in chronically demyelinated mice, a model of multiple sclerosis. The cellular antigen for HIgM12 was undetermined. Here, we identified polysialic acid attached to NCAM (neural cell adhesion molecule) as the cellular target for HIgM12. This includes glial fibrillary acidic protein (GFAP)-positive mouse astrocytes (GFAP, red; HIgM12, green; DAPI, blue) among other cell types of the central nervous system. These findings indicate a new strategy for the treatment of neuro-motor disorders including multiple sclerosis.

Monocyte HLA-DR expression and neutrophil CD64 expression as biomarkers of infection in critically ill neonates and infants.

BACKGROUND: Reduced monocyte HLA-DR expression and increased neutrophil CD64 expression have been proposed as biomarkers of infection. METHODS: From 2009-2011, blood samples from neonatal intensive care unit (NICU) and pediatric intensive care unit (ICU) patients <1 y of age were collected at enrollment and during subsequent evaluation for suspected infection, if it occurred. Samples were analyzed for monocyte HLA-DR and neutrophil CD64 expression levels by flow cytometry. RESULTS: Forty-seven infants had study samples collected at enrollment; 26 infants had study samples collected at the time of a suspected infection. At enrollment, there was an inverse relationship between neutrophil CD64 expression and age (P ≤ 0.047). At the time of suspected infection, infants with an infection demonstrated a lower percentage of HLA-DR+ monocytes (P = 0.02, area under the curve (AUC) 0.78), higher percentage of CD64+ neutrophils (P = 0.009, AUC 0.81), and higher neutrophil CD64 expression levels (P = 0.04, AUC 0.75). CONCLUSION: Monocyte HLA-DR and neutrophil CD64 expression in critically ill infants are related to age and infection.

Survival of outborns with congenital diaphragmatic hernia: the role of protective ventilation, early presentation and transport distance: a retrospective cohort study.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a congenital malformation associated with life-threatening pulmonary dysfunction and high neonatal mortality. Outcomes are improved with protective ventilation, less severe pulmonary pathology, and the proximity of the treating center to the site of delivery. The major CDH treatment center in Croatia lacks a maternity ward, thus all CDH patients are transferred from local Zagreb hospitals or remote areas (outborns). In 2000 this center adopted protective ventilation for CDH management. In the present study we assess the roles of protective ventilation, transport distance, and severity of pulmonary pathology on survival of neonates with CDH. METHODS: The study was divided into Epoch I, (1990-1999, traditional ventilation to achieve normocapnia), and Epoch II, (2000-2014, protective ventilation with permissive hypercapnia). Patients were categorized by transfer distance (local hospital or remote locations) and by acuity of respiratory distress after delivery (early presentation-occurring at birth, or late presentation, ≥ 6 h after delivery). Survival between epochs, types of transfers, and acuity of presentation were assessed. An additional analysis was assessed for the potential association between survival and end-capillary blood CO2 (PcCO2), an indirect measure of pulmonary pathology. RESULTS: There were 83 neonates, 26 in Epoch I, and 57 in Epoch II. In Epoch I 11 patients (42%) survived, and in Epoch II 38 (67%) (P = 0.039). Survival with early presentation (N = 63) was 48 % and with late presentation 95% (P <0.001). Among early presentation, survival was higher in Epoch II vs. Epoch I (57% vs. 26%, P = 0.031). From multiple logistic regression analysis restricted to neonates with early presentation and adjusting for severity of disease, survival was improved in Epoch II (OR 4.8, 95%CI 1.3-18.0, P = 0.019). Survival was unrelated to distance of transfer but improved with lower partial pressure of PcCO2 on admission (OR 1.16, 95%CI 1.01-1.33 per 5 mmHg decrease, P = 0.031). CONCLUSIONS: The introduction of protective ventilation was associated with improved survival in neonates with early presentation. Survival did not differ between local and remote transfers, but primarily depended on severity of pulmonary pathology as inferred from admission capillary PcCO2.

Predictive Ability of Direct Antibody Testing in Infants Born to Mothers with Rh(D) and Other Minor Red Blood Cell Antibodies.

OBJECTIVE: Hemolytic disease of the newborn (HDN) most commonly occurs in neonates whose mothers carry nonpassively acquired antibodies directed against red blood cell (RBC) antigens. Because affected neonates may develop severe hyperbilirubinemia, early identification of at-risk neonates is critically important. We hypothesized that use of the direct antibody test (DAT) would be of high predictive value in identifying those neonates most likely to meet treatment criteria for hyperbilirubinemia. STUDY DESIGN: We performed a retrospective chart review of all mother-infant pairs in which RBC antibodies were detected on routine prenatal screening during the current pregnancy (2011-2013). We then compared DAT results of neonates who eventually met the treatment criteria for hyperbilirubinemia with those who did not. MAIN RESULTS: Fifty-sixty neonates were born to mothers with clinically significant antibodies. The sensitivity and specificity of a positive DAT result for meeting the treatment criteria were 87.5 and 93.3%, respectively. The positive and negative predictive values were 77.8 and 96.6%, respectively. CONCLUSION: The result of a DAT, obtained in neonates of mothers with clinically relevant alloantibodies, is a specific marker with good positive predictive value for identifying those who are most likely to meet the treatment criteria for hyperbilirubinemia.

Superior mesenteric artery blood flow velocities following medical treatment of a patent ductus arteriosus.

We examined superior mesenteric artery blood flow velocity in response to feeding in infants randomized to trophic feeds (n = 16) or nil per os (n = 18) during previous treatment for patent ductus arteriosus. Blood flow velocity increased earlier in the fed infants, but was similar in the 2 groups at 30 minutes after feeding.

Heart-rate-corrected QT interval evolution in premature infants during the first week of life.

Automated monitoring of the QT interval is increasingly common in a variety of clinical settings. A better understanding of how the heart-rate-corrected QT interval (QTc) evolves in early postnatal life is needed before its clinical utility in neonates can be determined. This study aimed to use real-time bedside monitoring as a tool to describe the QTc evolution of premature neonates during the first week of life. All neonates born at a gestation age (GA) of 31 weeks or later and admitted to the level 2 intensive care nursery of the authors' institution between December 2012 and March 2013 were included in this study. The authors prospectively collected QTc values at 15-min intervals during the first week of life, then used two-way analysis of variance (ANOVA) to compare these data among three GA cohorts: 31 to <34 weeks (cohort A), 34 to <37 weeks (cohort B), and ≥37 weeks (cohort C). All the cohorts demonstrated a statistically significant decline in the 24-h average QTc during the first 3-4 days of life before reaching a stable baseline. No diurnal variation in the QTc was identified in any of the study patients. Marked variability and a progressive decline in the QTc of premature neonates occur during the first 3-4 days of life. Understanding this phenomenon is imperative when screening programs for the early detection of QT prolongation are considered.

Perceptions and practices of therapeutic hypothermia in American neonatal intensive care units.

OBJECTIVE: In 2005, therapeutic hypothermia (TH) was used in few American neonatal intensive care units (NICUs) with great variability in practices. We hypothesized that TH would be used with greater frequency and uniformity today. STUDY DESIGN: We surveyed directors of 797 NICUs queried in our prior study to determine attitudes toward and practices of TH. RESULTS: Of the 781 participants with valid addresses, we received completed surveys from 330 (42.3%). There was an increase in the number of respondents who believed that TH is effective (85% versus 31%, p < 0.0001). More NICUs used TH (50% versus 6%, p < 0.0001) and nearly all not offering TH transferred eligible neonates to centers that did (97% versus 29%, p < 0.0001). There has been increased standardization of TH practices with regard to enrollment criteria, duration, and methods of monitoring. CONCLUSION: TH has become standard of care for the treatment of HIE in the United States. Most NICUs that use TH adhere to protocols, but variation still exists in TH practices.

A Flipped Classroom Pilot in Neonatal Mechanical Ventilation.

Background: Pediatric residents frequently manage critically ill neonates but have limited systematic training in mechanical ventilation (MV). Competing demands, varying learner levels, and topic complexity contribute to inconsistent education. A blended learning approach may be ideally suited to achieve meaningful learning but has not been described for this topic and learner. Objective: To design, implement, and evaluate a flipped classroom for pediatric residents in neonatal MV. Methods: We used Kern's six-step framework for curricular development to create a flipped classroom curriculum in neonatal MV. Individual prework included interaction with six prerecorded animated whiteboard videos, while in-person learning occurred in small groups at the bedside of a ventilated infant. A mixed-methods evaluation included surveys, quantitative knowledge test scores (before, immediately after, and six months after course completion), and qualitative analysis of participant focus groups. Results: Twenty-six learners participated in the curriculum. Mean knowledge test scores rose and were sustained after course completion (51% baseline, 82% immediate posttest, 90% retention; P < 0.001). Learners identified various design elements, technology affordances, and instructor factors as meaningful, and they identified unexpected impacts of the curriculum beyond knowledge acquisition, including effects on professional identities, interdisciplinary communication skills, and contribution to the culture of safety. Conclusion: This curriculum aligned with resident roles, was meaningful to learners, and led to long-term increases in knowledge scores and access to quality education; flipped classroom design using meaningful learning theory and leveraging animated whiteboard technology may be a useful strategy for other highly complex topics in graduate medical education.

Enteral feeding during indomethacin and ibuprofen treatment of a patent ductus arteriosus.

OBJECTIVE: To test the hypothesis that infants who are just being introduced to enteral feedings will advance to full enteral nutrition at a faster rate if they receive "trophic" (15 mL/kg/d) enteral feedings while receiving indomethacin or ibuprofen treatment for patent ductus arteriosus. STUDY DESIGN: Infants were eligible for the study if they were 23(1/7)-30(6/7) weeks' gestation, weighed 401-1250 g at birth, received maximum enteral volumes ≤60 mL/kg/d, and were about to be treated with indomethacin or ibuprofen. A standardized "feeding advance regimen" and guidelines for managing feeding intolerance were followed at each site (N = 13). RESULTS: Infants (N = 177, 26.3 ± 1.9 weeks' mean ± SD gestation) were randomized at 6.5 ± 3.9 days to receive "trophic" feeds ("feeding" group, n = 81: indomethacin 80%, ibuprofen 20%) or no feeds ("fasting [nil per os]" group, n = 96: indomethacin 75%, ibuprofen 25%) during the drug administration period. Maximum daily enteral volumes before study entry were 14 ± 15 mL/kg/d. After drug treatment, infants randomized to the "feeding" arm required fewer days to reach the study's feeding volume end point (120 mL/kg/d). Although the enteral feeding end point was reached at an earlier postnatal age, the age at which central venous lines were removed did not differ between the 2 groups. There were no differences between the 2 groups in the incidence of infection, necrotizing enterocolitis, spontaneous intestinal perforation, or other neonatal morbidities. CONCLUSION: Infants required less time to reach the feeding volume end point if they were given "trophic" enteral feedings when they received indomethacin or ibuprofen treatments.