Cholestasis is associated with a higher rate of complications in both medical and surgical necrotizing enterocolitis.

OBJECTIVE: To evaluate the relationship between cholestasis and outcomes in medical and surgical necrotizing enterocolitis (NEC). STUDY DESIGN: A retrospective analysis of prospectively collected data from 1472 infants with NEC [455 medical (mNEC) and 1017 surgical (sNEC)] from the Children's Hospital Neonatal Database. RESULTS: The prevalence of cholestasis was lower in mNEC versus sNEC (38.2% vs 70.1%, p < 0.001). In both groups, cholestasis was associated with lower birth gestational age [mNEC: OR 0.79 (95% CI 0.68-0.92); sNEC: OR 0.86 (95% CI 0.79-0.95)] and increased days of parenteral nutrition [mNEC: OR 1.08 (95% CI 1.04-1.13); sNEC: OR 1.01 (95% CI 1.01-1.02)]. For both groups, the highest direct bilirubin was associated with the composite outcome mortality or length of stay >75th percentile [mNEC: OR 1.21 (95% CI 1.06-1.38); sNEC: OR 1.06 (95% CI 1.03-1.09)]. CONCLUSION: Cholestasis with both medical NEC and surgical NEC is associated with adverse patient outcomes including increased mortality or extreme length of stay.

Patterns of lipid-injectable emulsion use in neonatal intensive care units across the United States: A multi-institution survey.

BACKGROUND: Lipid-injectable emulsions (ILEs) are a necessity for neonates dependent on parenteral nutrition (PN). In this manuscript, we describe the patterns of ILE use in neonatal intensive care units (NICUs) in the United States (US). METHODS: An electronic survey was sent to 488 NICUs across the US between December 2020 and March 2021. Survey fields included availability and utilization of various ILE in neonates. RESULTS: The response rate was 22% (107 out of 488). Soybean oil ILE (SO-ILE) and soybean oil, medium-chain triglycerides, olive oil, fish oil ILE (SO, MCT, OO, FO-ILE) had similar availability (87% vs 86%, respectively), and SO, MCT, OO, FO-ILE was more commonly used (SO-ILE, 71% vs SO, MCT, OO, FO-ILE, 86%). Fish oil-ILE (FO-ILE) was used by 55% of centers. SO-ILE was most frequently used with PN and needs <4 weeks without cholestasis (79%). The most common reason for SO, MCT, OO, FO-ILE use was cholestasis (71%). ILE minimization was used by 28% of SO-ILE and 22% of SO, MCT, OO, FO-ILE users; 95% of these centers restrict SO, MCT, OO, FO-ILE to doses ≤2 g/kg/day. Twenty-two percent of centers started FO-ILE at direct bilirubin of >5 mg/dl. CONCLUSION: The results of this survey reveal significant variability in ILE usage across the US. Lipid minimization with SO, MCT, OO, FO-ILE and initiation of FO-ILE for cholestasis at higher bilirubin thresholds are prevalent. Such reports are crucial for a better understanding of ILE use in the NICU and in future ILE development.

Variability in antibiotic duration for necrotizing enterocolitis and outcomes in a large multicenter cohort.

OBJECTIVES: To evaluate variability in antibiotic duration for necrotizing enterocolitis (NEC) and associated clinical outcomes. STUDY DESIGN: Five-hundred ninety-one infants with NEC (315 medical; 276 surgical) were included from 22 centers participating in Children's Hospitals Neonatal Consortium (CHNC). Multivariable analyses were used to determine predictors of variability in time to full feeds (TFF) and length of stay (LOS). RESULTS: Median (IQR) antibiotic duration was 12 (9, 17) days for medical and 17 (14, 21) days for surgical NEC. Wide variability in antibiotic use existed both within and among centers. Duration of antibiotic therapy was associated with longer TFF in both medical (OR 1.04, 95% CI [1.01, 1.05], p < 0.001) and surgical NEC (OR 1.02 [1, 1.03] p = 0.046); and with longer LOS in medical (OR 1.03 [1.02, 1.04], p < 0.001) and surgical NEC (OR 1.01 [1.01, 1.02], p = 0.002). CONCLUSION: Antibiotic duration for both medical and surgical NEC remains variable within and among high level NICUs.

Part 6: Essentials of Neonatal-Perinatal Medicine fellowship: program administration.

A successful Neonatal-Perinatal Medicine fellowship (NPM-F) program requires presence and insight of national and institutional supervisory organizations as well as effective program-specific leaders: program director (PD), associate program director (APD), program coordinator (PC), and core faculty. It is becoming more common for PDs and APDs to have advanced training in medical education and conduct medical education research. While NPM-F program leaders benefit from a strong national NPM educator community, they face challenges of increased regulatory burden and unclear national guidelines with variable local interpretation for protected time. National and local organizations can support program leaders and promote their academic success while reducing burnout and turnover by providing leadership training, academic mentoring, and adequate protected time for research and program-specific tasks.

Neonatal respiratory extracorporeal membrane oxygenation and primary diagnosis: trends between two decades.

OBJECTIVE: Examine changing neonatal respiratory extracorporeal membrane oxygenation (ECMO) practice trends and outcomes. STUDY DESIGN: Retrospective cohort study comparing neonatal respiratory ECMO in the 1990 and 2010 decades (1994-1995 and 2014-2015). Patients ≤ 30 days of life, reported to the Extracorporeal Life Support Organization registry, were included. RESULTS: Four thousand one hundred and twenty-five patients met inclusion criteria. ECMO cases decreased by 33%. The primary ECMO diagnosis changed significantly over time (p < 0.0001). Survival to discharge decreased (76 vs 67%, p < 0.0001) and ECMO duration increased (131 vs 158 h, p < 0.001). Lung recovery was the most common reason to discontinue ECMO although family request for withdrawal and a diagnosis considered "incompatible with life" was increasingly common in the 2010s. CONCLUSION: Although the use of ECMO for neonatal respiratory diagnoses has decreased over time, its use has increased for patients with more complex diagnoses and ECMO duration is longer. ECMO continues to be an important supportive therapy, improved understanding of which patients would benefit most is needed.

Families as educators: a family-centered approach to teaching communication skills to neonatology fellows.

OBJECTIVE: To determine whether the use of family members as educators in a structured educational intervention would increase neonatology fellows' confidence in performing core communication skills targeted to guide family decision-making. STUDY DESIGN: Neonatology fellows at two centers participated in simulation-based training utilizing formally trained family members of former patients. Fellows completed self-assessment surveys before participating, immediately following participation, and 1-month following the training. Family members also evaluated fellow communication. RESULTS: For each core competency assessed, there was a statistically significant increase in self-perceived preparedness from pre-course to post-course assessments. Fellows additionally endorsed using skills learned in the curriculum in daily clinical practice. Family educators rated fellow communication highest in empathetic listening and nonverbal communication. CONCLUSIONS: Participation in a communication skills curriculum utilizing formally trained family members as educators for medical trainees successfully increased fellows' self-perceived preparedness in selected core competencies in communication. Family educators provided useful, generalizable feedback.

Does the initial surgery for necrotizing enterocolitis matter? Comparative outcomes for laparotomy vs. peritoneal drain as initial surgery for necrotizing enterocolitis in infants <1000 g birth weight.

PURPOSE: Quantify short-term outcomes associated with initial surgery [laparotomy (LAP) vs. peritoneal drain (PD)] for necrotizing enterocolitis (NEC) in extremely-low-birth-weight (ELBW) infants. METHODS: Using the Children's Hospitals Neonatal Database, we identified ELBW infants <32 weeks' gestation with surgical NEC (sNEC). Unadjusted and multivariable regression analyses were used to estimate the associations between LAP (or PD) and death/short bowel syndrome (SBS) and length of stay (LOS). RESULTS: LAP was the more common initial procedure for sNEC (n = 359/528, 68%). Infants receiving LAP were older and heavier. Initial procedure was unrelated to death/SBS in both bivariate (LAP: 43% vs PD: 46%, p = 0.573) and multivariable analyses (OR = 0.89, 95% CI = 0.57, 1.38, p = 0.6). LAP was inversely related to mortality (29% vs. 41%, p < 0.007) in bivariate analysis, but not significant in multivariable analysis accounting for markers of preoperative illness severity. However, the association between LAP and SBS (14% vs. 5%, p = 0.012) remained significant in multivariable analyses (adjusted OR = 2.25, p = 0.039). LOS among survivors was unrelated to the first surgical procedure in multivariable analysis. CONCLUSION: ELBW infants who undergo LAP as the initial operative procedure for sNEC may be at higher risk for SBS without a clear in-hospital survival advantage or shorter hospitalization. LEVEL OF EVIDENCE: Level II.

A Singleton Infant with Bilateral Renal Agenesis and Normal Pulmonary Function.

Bilateral renal agenesis leads to anhydramnios and other sequelae including pulmonary hypoplasia. There have been rare case reports of normal pulmonary function in the presence of bilateral renal agenesis in monoamniotic discordant twins, but this has never been reported in a singleton pregnancy. The few reported cases in twins have all been fatal in the neonatal period with no reported cases of survival beyond 2 months. We describe the first case of a singleton infant with bilateral renal agenesis who had normal pulmonary function and did well on peritoneal dialysis for 4 years while awaiting a renal transplant.

Delivering Difficult News and Improving Family Communication: Simulation for Neonatal-Perinatal Fellows.

INTRODUCTION: This 3-hour simulation module provides a safe situation for neonatal-perinatal fellows to learn communication techniques and develop skills for delivering difficult news to patients' families. These skills are critical for a practicing neonatologist in an academic or private-practice setting yet are often underrepresented in the educational content of training programs. This module is intended for fellows who have had basic communication skills instruction, as well as interactions with parents as part of their pediatric residency training. METHODS: The fellows practice delivering difficult news by interacting with standardized parents in scenarios designed for one to three learners at a time. Each scenario runs for approximately 10 to 15 minutes and is followed by a 25- to 30-minute debriefing. Those not participating in the scenario view the simulation in real-time video broadcast from another room so they can learn from the scenario and participate in the debriefing. The module also includes 10 to 15 minutes for discussion of literature. This publication includes an introductory slide presentation and a comprehensive compilation of communication recommendations from attending neonatologists. Also included are scripts for the standardized parents, background information for learners, guidelines and suggestions for discussion during the debriefing, and an evaluation form. RESULTS: This module has been incorporated into the yearly simulation curriculum for our neonatal-perinatal fellowship. After completing the module, fellows have reported feeling more comfortable with delivering difficult news. The average score in fellows' comfort level for having these conversations rose from 5.8 to 7.5 on a 10-point scale. DISCUSSION: This module was designed for use in a perinatal-neonatal fellowship training program, but it could be used in all pediatric residencies, as well as for support staff training (social work, nursing, chaplaincy) with the use of a confederate physician.

How infants die in the neonatal intensive care unit: trends from 1999 through 2008.

OBJECTIVE: To determine whether trends toward decreasing use of cardiopulmonary resuscitation at the time of death and increasing frequency of forgoing life-sustaining treatment had continued, as few studies quantifying mode of death for hospitalized infants have been conducted in the last 10 years. DESIGN: Retrospective descriptive study. SETTING: Regional referral neonatal intensive care unit. PARTICIPANTS: Infants who died from January 1, 1999, to December 31, 2008. Infants were categorized into following categories: (1) very preterm (≤32 weeks' gestation); (2) congenital anomaly; and (3) other. MAIN OUTCOME MEASURES: The primary outcome was level of clinical service provided at the end of life (care withheld, care withdrawn, or full resuscitation). RESULTS: For 10 years, 414 neonatal patients died. Of these, 61.6% had care withdrawn, 20.8% had care withheld, and 17.6% received cardiopulmonary resuscitation. The percentage of deaths that followed withholding of treatment rose by 1% per year (P = .01). Most of this change was accounted for by withholding of therapy in the very premature group. CONCLUSION: During the 10-year period, the primary mode of death in this regional referral neonatal intensive care unit was withdrawal of life-sustaining support. When death is imminent or medical care is considered futile, the approach is thought to provide a peaceful, controlled setting. Significant increase in withholding of care suggests improved recognition of medical futility and desire to provide a peaceful death.

Captopril and vascular endothelial growth factor in a mouse model of retinopathy.

PURPOSE: Angiotensin converting enzyme (ACE) inhibition has been shown in animal models of retinopathy and in patients with diabetes to improve retinal neovascularization. The mechanism is not clearly identified, but could potentially be mediated via vascular endothelial growth factor modification. The objective of this study was to determine the effect of captopril, an angiotensin converting enzyme (ACE) inhibitor, on retinal VEGF, VEGF-R1, and VEGF-R2 expression in a mouse model of oxygen induced retinopathy (OIR). METHODS: A mouse model of OIR was used and retinal tissue was obtained at P7, prior to oxygen exposure, at P12, just after oxygen exposure, and at P17, the time of maximal retinal neovascularization for VEGF, VEGF-R1 and VEGF-R2 assessment. A group of animals were treated with captopril (0.5 mg/kg/d SC from P7 for five days). RESULTS: Captopril plus OIR treated animals had higher levels of retinal VEGF mRNA and protein at P12 (p < 0.05) and lower levels at P17 (p < 0.05) than OIR animals. VEGF-R1 mRNA expression increased 16 fold from P7 to P17 (p < 0.05) in room air reared animals. VEGF-R1 mRNA expression was unaffected by OIR and/or captopril treatment. VEGF-R2 mRNA expression decreased from P7 to P17 by 1.5-fold in room air reared animals (p = 0.001). Retinal VEGF-R2 mRNA and protein expression were significantly higher at P12 in OIR plus captopril treated animals than OIR animals (p = 0.01). CONCLUSIONS: In summary, captopril maintains VEGF and increases VEGF-R2 expression during the period of hyperoxia when VEGF expression is normally suppressed. Captopril treatment during oxygen exposure is associated with a reduction in the angiogenic response at day 17 as manifested by decreased VEGF and VEGF-R2 expression in retinal tissue. Angiotensin converting enzyme inhibition is associated with changes in expression of VEGF and VEGF-R2 in the evolution of retinal neovascularization in the mouse model of retinopathy.

Ibuprofen improves oxygen-induced retinopathy in a mouse model.

PURPOSE: Retinopathy of prematurity is a developmental vascular anomaly occurring in the incompletely vascularized retina of the premature infant. Ibuprofen is a nonsteroidal anti-inflammatory agent similar to indomethacin, but with less pronounced side-effects. The goal of the study was to test the hypothesis that ibuprofen would improve oxygen-induced retinopathy in a mouse model. METHODS: C57BL6 mice pups were exposed to 75% oxygen from postnatal day 7 through postnatal day 12. Ibuprofen was administered along with oxygen exposure as a single subcutaneous dose of 40 mg/kg/day for 5 days. Animals were sacrificed on postnatal day 17 through postnatal day 20. The severity of retinopathy was assessed by a retinopathy scoring system of fluorescein-conjugated dextran-perfused retinal flat mounts and by quantitation of extra-retinal nuclei by use of periodic acid-Schiff-stained retinal sections. RESULTS: Animals that received ibuprofen during hyperoxia exposure had a significantly lower median (25th, 75th quartile) retinopathy score of 6 (5, 7.5) compared with animals that received oxygen only, with a score of 12 (10.5, 12.5), with p < 0.005. Animals given ibuprofen during hyperoxia exposure had a significantly lower extra-retinal nuclei count per section (14.2 +/- 3.6) compared with animals that were only exposed to oxygen (26.8 +/- 5.8), with p < 0.005. Ibuprofen did not affect the growth of the animals. CONCLUSION: Ibuprofen improves oxygen-induced retinopathy when administered concurrently with the injury phase without affecting the normal retinal development of the animals.