Jonathan L. Slaughter

Vitamin D status of early preterm infants and the effects of vitamin D intake during hospital stay.

Objectives To evaluate vitamin D (vitD) status in early preterm infants (EPTIs) at birth and during birth hospitalisation on current vitD intake. Design/methods Serum 25-hydroxyvitamin-D [25(OH)D] concentrations, vitD intake and risk factors for low vitD status were assessed in 120 infants born at ≤32 weeks gestation. Results Mean (SD) serum 25(OH)D at birth was 46.2 (14.0) nmol/L with lower concentrations in infants born <28 weeks than at 28–32 weeks gestation, p=0.02. Serum 25(OH)D was <50 nmol/L in 63% of mothers, 64% of infants at birth and 35% of infants at discharge. Mean daily vitD intake was 289±96 IU at 4 weeks of age and 60% achieved 400 IU/day intake at discharge. Conclusions Serum 25(OH)D <50 nmol/L was widespread in parturient women and in EPTIs at birth and at discharge. Optimising maternal vitD status during pregnancy and improving postnatal vitD intake may enhance infant vitD status during hospitalisation.

Pharmacological Treatment of Neonatal Seizures: A Systematic Review

Pharmacologic treatment options for neonatal seizures have expanded over the past 2 decades, and there is no consensus on optimal treatment strategy. We systematically reviewed the published literature to determine which medication(s) are most effective for treating neonatal seizures, by retrieving trials and observational investigations via PubMed (through August 2011) that focused on pharmacological seizure treatment of neonates (≤ 28 days old) and utilized continuous or amplitude-integrated EEG to confirm seizure diagnosis and cessation. Our search identified 557 initial articles and 14 additional studies after reference reviews, with 16 meeting inclusion criteria. Of these, 2 were randomized trials and only 3 additional investigations included comparison groups. We found limited evidence regarding the best pharmacologic treatment for neonatal seizures, but were able to devise a treatment algorithm from available data. These findings have the potential to serve as a clinical reference and to inform the design of comparative effectiveness investigations for neonatal antiepileptics.

Variation in the Use of Diuretic Therapy for Infants With Bronchopulmonary Dysplasia

OBJECTIVES: To determine (1) between-hospital variation in diuretic use for infants with bronchopulmonary dysplasia (BPD), including hospital-specific treatment frequency, treatment duration, and percentage of infants receiving short (≤5 consecutive days) versus longer (>5 days) courses, and to determine (2) demographic and clinical variables associated with diuretic administration. METHODS: A retrospective cohort study was conducted with the use of the Pediatric Health Information System to determine between-hospital variation in diuretic utilization patterns (primary outcome) and variables associated with diuretic use among <29-week-gestation infants with evolving BPD at age 28 days who were discharged between January 2007 and June 2011. RESULTS: During the 54-month study period, 1429 infants within 35 hospitals met the inclusion criteria for BPD at age 28 days, with 1222 (86%) receiving diuretic therapy for a median of 9 days (25th–75th percentile: 2–33 days). Short courses were administered to 1203 (83%) infants, and 570 (40%) infants received treatment for >5 consecutive days. Furosemide was the most widely prescribed diuretic (1218 infants; 85%), although chlorothiazide had the longest median duration of use (21 days; 25th–75th percentile: 8–46 days). The range of infants receiving a diuretic course of >5 days duration varied by hospital from 4% to 86%, with wide between-hospital variation even after adjustment for confounding variables. CONCLUSIONS: The frequency of diuretic administration to infants with BPD at US children’s hospitals, as well as the specific diuretic regimen used, varies markedly by institution. Safety and effectiveness research of long-term diuretic therapy for BPD patients is needed to develop evidence-based recommendations.

Utilization of Inhaled Corticosteroids for Infants with Bronchopulmonary Dysplasia

Objective To determine demographic and clinical variables associated with inhaled corticosteroid administration and to evaluate between-hospital variation in inhaled steroid use for infants with bronchopulmonary dysplasia (BPD). Design Retrospective Cohort Study. Setting Neonatal units of 35 US childrens hospitals; as recorded in the Pediatric Health Information System (PHIS) database. Patients 1429 infants with evolving BPD at 28 days who were born at <29 weeks gestation with birth weight <1500 grams, admitted within the first 7 postnatal days, and discharged between January 2007–June 2011. Results Inhaled steroids were prescribed to 25% (n = 352) of the cohort with use steadily increasing during the first two months of hospitalization. The most frequently prescribed steroid was beclomethasone (n = 194, 14%), followed by budesonide (n = 125, 9%), and then fluticasone (n = 90, 6%). Birth gestation <24 weeks, birth weight 500–999 grams, and prolonged ventilation all increased the adjusted odds of ever receiving inhaled corticosteroids (p<0.05). Wide variations between hospitals in the frequency of infants ever receiving inhaled steroids (range: 0–60%) and the specific drug prescribed were noted. This variation persisted, even after controlling for observed confounders. Conclusions Inhaled corticosteroid administration to infants with BPD is common in neonatal units within U.S. Childrens hospitals. However, its utilization varies markedly between centers from no treatment at some institutions to the majority of infants with BPD being treated at others. This supports the need for further research to identify the benefits and potential risks of inhaled steroid usage in infants with BPD.

Systematic Review of Inhaled Bronchodilator and Corticosteroid Therapies in Infants with Bronchopulmonary Dysplasia: Implications and Future Directions

Background There is much debate surrounding the use of inhaled bronchodilators and corticosteroids for infants with bronchopulmonary dysplasia (BPD). Objective The objective of this systematic review was to identify strengths and knowledge gaps in the literature regarding inhaled therapies in BPD and guide future research to improve long-termoutcomes. Methods The databases of Academic Search Complete, CINAHL, PUBMED/MEDLINE, and Scopus were searched for studies that evaluated both acute and long-term clinical outcomes related to the delivery and therapeutic efficacy of inhaled beta-agonists, anticholinergics and corticosteroids in infants with developing and/or established BPD. Results Of 181 articles, 22 met inclusion criteria for review. Five evaluated beta-agonist therapies (n = 84, weighted gestational age (GA) of 27.1(26–30) weeks, weighted birth weight (BW) of 974(843–1310) grams, weighted post menstrual age (PMA) of 34.8(28–39) weeks, and weighted age of 53(15–86) days old at the time of evaluation). Fourteen evaluated inhaled corticosteroids (n = 2383, GA 26.2(26–29) weeks, weighted BW of 853(760–1114) grams, weighted PMA of 27.0(26–31) weeks, and weighted age of 6(0–45) days old at time of evaluation). Three evaluated combination therapies (n = 198, weighted GA of 27.8(27–29) weeks, weighted BW of 1057(898–1247) grams, weighted PMA of 30.7(29–45) weeks, and age 20(10–111) days old at time of evaluation). Conclusion Whether inhaled bronchodilators and inhaled corticosteroids improve long-term outcomes in BPD remains unclear. Literature regarding these therapies mostly addresses evolving BPD. There appears to be heterogeneity in treatment responses, and may be related to varying modes of administration. Further research is needed to evaluate inhaled therapies in infants with severe BPD. Such investigations should focus on appropriate definitions of disease and subject selection, timing of therapies, and new drugs, devices and delivery methods as compared to traditional methods across all modalities of respiratory support, in addition to the assessment of long-term outcomes of initial responders.

Comparative Effectiveness of Nonsteroidal Anti-inflammatory Drug Treatment vs No Treatment for Patent Ductus Arteriosus in Preterm Infants

Importance Patent ductus arteriosus (PDA) is associated with increased mortality and worsened respiratory outcomes, including bronchopulmonary dysplasia (BPD), in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in closing PDA, but the effectiveness of NSAID-mediated PDA closure in improving mortality and preventing BPD is unclear. Objective To determine the effectiveness of NSAID treatment for PDA in reducing mortality and moderate/severe BPD at 36 weeks postmenstrual age. Design, Setting, and Participants This cohort study included 12 018 infants born at 28 gestational weeks or younger discharged between January 2006 and December 2013 from neonatal intensive care units in 25 US children’s hospitals included in the Pediatric Health Information System. We performed an instrumental variable analysis that incorporated clinician preference–based, institutional variation in NSAID treatment frequency to determine the effect of NSAID treatment for PDA on mortality and BPD. Exposures Proportion of NSAID-treated infants born at each infant’s institution within ±6 months of that infant’s birth. Main Outcomes and Measures The primary composite outcome was death, moderate, or severe BPD at 36 weeks postmenstrual age. Results Of the 6370 male and 5648 female infants in this study, 4995 (42%) were white, 3176 (26%) were African American, 1823 (15%) were Hispanic, and 1555 (13%) were other races/ethnicities. The proportion of NSAID-treated infants at each infants hospital within ±6 months of that infants birth was associated with NSAID treatment and not associated with gestation, race/ethnicity, or sex. An infant’s chances of receiving NSAID treatment increased by 0.84% (95% CI, 0.8-0.9; P < .001) for every 1% increase in the annual NSAID treatment percentage at a given hospital. An instrumental variable analysis demonstrated no association between NSAID treatment and the odds of mortality or BPD (odds ratio, 0.94; 95% CI, 0.70-1.25; P = .69), mortality (odds ratio, 0.73; 95% CI, 0.43-1.13; P = .18), or BPD (odds ratio, 1.01; 95% CI, 0.73-1.45; P = .94) in survivors. Conclusions and Relevance When we incorporated clinician preference–based practice variation as an instrument to minimize the effect of unmeasured confounding, we detected no changes in the odds of mortality or moderate/severe BPD among similar preterm infants born at 28 weeks or younger following NSAID treatment for PDA initiated 2 to 28 days postnatally. Our findings agree with available randomized clinical trial evidence and support a conservative approach to PDA management.

Effect of nasal noninvasive respiratory support methods on pharyngeal provocation-induced aerodigestive reflexes in infants

The pharynx is a locus of provocation among infants with aerodigestive morbidities manifesting as dysphagia, life-threatening events, aspiration-pneumonia, atelectasis, and reflux, and such infants often receive nasal respiratory support. We determined the impact of different oxygen delivery methods on pharyngeal stimulation-induced aerodigestive reflexes [room air (RA), nasal cannula (NC), and nasal continuous positive airway pressure (nCPAP)] while hypothesizing that the sensory motor characteristics of putative reflexes are distinct. Thirty eight infants (28.0 ± 0.7 wk gestation) underwent pharyngoesophageal manometry and respiratory inductance plethysmography to determine the effects of graded pharyngeal stimuli (n = 271) on upper and lower esophageal sphincters (UES, LES), swallowing, and deglutition-apnea. Comparisons were made between NC (n = 19), nCPAP (n = 9), and RA (n = 10) groups. Importantly, NC or nCPAP (vs. RA) had: 1) delayed feeding milestones (P < 0.05), 2) increased pharyngeal waveform recruitment and duration, greater UES nadir pressure, decreased esophageal contraction duration, decreased distal esophageal contraction amplitude, and decreased completely propagated esophageal peristalsis (all P < 0.05), and 3) similarly developed UES contractile and LES relaxation reflexes (P > 0.05). We conclude that aerodigestive reflexes were similarly developed in infants using noninvasive respiratory support with adequate upper and lower aerodigestive protection. Increased concern for GERD is unfounded in this population. These infants may benefit from targeted oromotor feeding therapies and safe pharyngeal bolus transit to accelerate feeding milestones.

Inhaled bronchodilator use for infants with bronchopulmonary dysplasia

Objective:To identify factors associated with bronchodilator administration to infants with bronchopulmonary dysplasia (BPD) and evaluate inter-institutional prescribing patterns.Study Design:A retrospective cohort study of <29-week-gestation infants with evolving BPD defined at age 28 days within the Pediatric Health Information System database. Controlling for observed confounding with random-effects logistic regression, we determined demographic and clinical variables associated with bronchodilator use and evaluated between-hospital variation.Result:During the study period, 33% (N=469) of 1429 infants with BPD received bronchodilators. Lengthening mechanical ventilation duration increased the odds of receiving a bronchodilator (odds ratio 19.6 (11 to 34.8) at ⩾54 days). There was profound between-hospital variation in use, ranging from 0 to 81%.Conclusion:Bronchodilators are frequently administered to infants with BPD at US children’s hospitals with increasing use during the first hospital month. Increasing positive pressure exposure best predicts bronchodilator use. Frequency and treatment duration vary markedly by institution even after adjustment for confounding variables.

Transient effects of transfusion and feeding advances (volumetric and caloric) on necrotizing enterocolitis development: A case-crossover study

Objective To evaluate the short-term effects of feed fortification, feed volume increase, and PRBC transfusion on the odds of developing NEC. Study design Case-crossover study of neonatal intensive care infants born at ≤ 32 weeks’ gestation who were admitted to 5 central Ohio intensive care units from January 2012-July 2016 and developed NEC Bell Stage ≥2. Each patient served as their own control, with exposure during the 48-hour period just prior to NEC onset (hazard period) being compared to a preceding 48-hour control period, thus eliminating confounding by patient factors fixed between both intervals. NEC onset was determined by chart review as the earliest occurrence of one of the following within 24 hours of confirmatory x-ray: (1) antibiotic initiation, (2) enteral feeding cessation, (3) physician first notified of abdominal concerns, or (4) abdominal x-ray ordered. Conditional logistic regression compared exposures to feed volume increase, fortification, and PRBC transfusion during the 48-hour period prior to NEC onset to those during a preceding 48-hour control period. Analyses were stratified by gestational age and anemia (defined: hemoglobin ≤ 9.3 g/dL within 7 days of NEC onset). Results We included 63 infants with confirmed NEC. Acute exposure to fortification (odds ratio [OR]: 1.67, 95% confidence interval [CI]: 0.61, 4.59), feed volume increase (OR: 0.63, 95% CI: 0.28, 1.38), and PRBC transfusion (OR: 1.80, 95% CI: 0.60, 5.37) was not associated with the onset of NEC. Gestational age and anemia did not significantly modify the associations. Sensitivity testing substituting 24- and 72-hour hazard and control periods produced similar results. Conclusion Using a case-crossover design, we did not detect an association between NEC development and feed fortification, feed volume increase, or PRBC transfusion within 48-hours prior to NEC-onset. Replication in a larger set of cases is needed.

Patterns of Empiric Antibiotic Administration for Presumed Early-Onset Neonatal Sepsis in Neonatal Intensive Care Units in the United States

Objective To evaluate current patterns in empiric antibiotic use for early‐onset neonatal sepsis (EONS). Study Design Retrospective population‐based cohort study of newborns admitted on postnatal day 0 to 1 and discharged from NICUs participating in the Pediatric Health Information System (PHIS 2006‐2013). Analyses included frequency of antibiotic initiation within 3 days of birth, duration of first course, and variation among hospitals. Results Of 158,907 newborns, 118,624 (74.7%) received antibiotics on or before postnatal day 3. Within 3 days of treatment, 49.4% (n = 58,610) were discharged home or remained hospitalized without antibiotics. There was marked interhospital variation in the proportion of infants receiving antibiotics (range: 52.3‐90.9%, mean 77.9%, SD 11.0%) and in treatment days (range: 3.2‐8.6, mean 5.3, SD 1.4). Facilities with higher number of newborns started on antibiotics had longer courses (r = 0.643, p < 0.001). The cost of admissions for infants born at ≥35 weeks started on antibiotics and discharged home after no more than 3 days of antibiotics was