Bronchopulmonary Dysplasia: Ongoing Challenges from Definitions to Clinical Care.

Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Its etiology is multifactorial and is attributed to genetic susceptibility to prenatal and postnatal factors. As advancements in neonatology have led to the increased survival of premature infants, a parallel increase in the incidence of BPD has occurred. Over time, the definition and diagnostic criteria for BPD have evolved, as have management strategies. However, challenges continue to exist in the management of these infants, which is not surprising given the complexity of the disease. We summarize the key diagnostic criteria and provide insight into the challenges related to various aspects of BPD definitions, data comparisons, and clinical care implementation.

Necrotizing enterocolitis in patients with congenital heart disease: A single center experience.

PURPOSE: The purpose of this study was to evaluate the characteristics of patients with congenital heart disease (CHD) who developed necrotizing enterocolitis (NEC). METHODS: A retrospective review of neonates with CHD at a tertiary care center between January 2006 and January 2016 was performed. Diagnosis of NEC was based on modified Bell's criteria. Patients were grouped by Risk Adjustment for Congenital Heart Surgery (RACHS-1) or by ductal-dependent (DD) lesions that require a patent ductus arteriosus to supply pulmonary or systemic circulation. RESULTS: Of 1811 neonates with CHD, 3.4% (n=61) developed NEC. Eighteen (30%) of these required surgical management. The rate of NEC among DD patients was 5% (n=33/653), compared to 2.4% (n=28/1158) in the non-DD group (p=0.003). RACHS-1 score>2 had a higher rate of NEC 6.2% (41/658) compared to RACHS-1≤2 cases, 1.7% (20/1153) (p=0.005). DD patients and complex patients with RACHS-1>2 were more likely to develop NEC after cardiac surgery. Hypoplastic left heart syndrome patients had a rate of 9% (n=16/185). Surgical NEC was more prevalent in the non-DD group. Mortality was similar among groups. CONCLUSION: CHD patients with ductal-dependent lesions or complex cases (RACHS-1 score>2) have higher rates of NEC than non-ductal-dependent patients or RACHS-1 score of 2 or less. Mortality is similar regardless of ductal dependence, but surgical NEC was more prevalent in non-DD patients. LEVEL OF EVIDENCE: Level IIb.

Immunostimulated Arginase II Expression in Intestinal Epithelial Cells Reduces Nitric Oxide Production and Apoptosis.

Increased production of nitric oxide (NO) and subsequent local cytotoxicity to mucosal epithelial cells has been proposed as a putative mechanism involved in the development of necrotizing enterocolitis (NEC). Intestinal epithelial cells (IECs) metabolize L-arginine to either nitric oxide (NO) by NO synthase (NOS) or to L-ornithine and urea by arginase. L-ornithine is the first step in polyamine synthesis important for cell proliferation, while NO production can lead to apoptosis. We hypothesized that in IECs immunostimulation increases both NOS and arginase expression, and that arginase activity mitigates NO production and apoptosis. Rat intestinal epithelial cells (rIEC-6) were immunostimulated by either incubation with lipopolysaccharide (LPS) alone for 24 h or by incubation with conditioned media (CM) for 24 h. CM was obtained from RAW 264.7 cells (a macrophage cell line) treated with LPS (E. coli 0127:B8; 1 µg/ml) for 4 h. The rIEC-6 stimulated with LPS or with CM had significantly higher levels of inducible NOS (iNOS) protein, NO production, and arginase II protein than did the control cells. Direct LPS stimulation of rIEC-6 produced a less robust increase in iNOS expression and NO (represented as nitrite percent of control) than did CM stimulation. Inhibition of arginase using Nω hydroxyl-L-arginine (NOHA) further increased stimulated NO production in rIEC-6. Viable cell numbers were significantly lower in CM stimulated cells after 24 h than in controls, and inhibition of arginase activity with NOHA resulted in a further significant decrease in viable cell numbers. We conclude that immunostimulated arginase expression of rIEC-6 cells tempers cytokine-induced iNOS-derived NO production and apoptosis.

The effect of supplemental parenteral nutrition on outcomes of necrotizing enterocolitis in premature, low birth weight neonates.

BACKGROUND: We hypothesized that supplemental parenteral nutrition (PN) decreases the need for surgery and mortality associated with necrotizing enterocolitis (NEC). METHODS: Single institution retrospective review of all premature, low birth weight infants with NEC from January 2006 to December 2013 was conducted. RESULTS: NEC was identified in 114 premature, low birth weight infants, 59 (51.8%) of which required surgical management. Surgical NEC infants were born younger (25.8 ± 4.0 vs 27.8 ± 3.3 weeks, P = .005) and weighed less at birth (829 ± 281 vs 938 ± 271 g, P = .038) than those managed medically. There was no difference in the use of PN (37.7% vs 31.4%, P = .541) between surgical and medical NEC patients. There was no statistically significant difference in mortality at discharge between patients who had PN at NEC onset and those who did not (31.4% vs 42.6%, P = .294) CONCLUSION: In this single-center study, supplemental PN at NEC onset does not appear to significantly improve outcomes as demonstrated by rates of surgical intervention and in-hospital mortality.

Safety and Efficacy of Oral Feeding in Infants with BPD on Nasal CPAP.

Safety and efficacy of oral feeding was examined in infants with bronchopulmonary dysplasia (BPD) on nasal continuous positive airway pressure (NCPAP). We hypothesized that repetitive oral feeding enhances aero-digestive outcomes and reduces resource utilization. Data from infants with BPD (37-42 weeks post menstrual age) that were orally fed while on NCPAP (n = 26) were compared with those that were exclusively gavage fed on NCPAP (n = 27). Subject assignment was random and physician practice based. Specifically, we compared the differences in aero-digestive milestones, resource utilization, and safety metrics. Demographic characteristics such as gender distribution, gestational age, and birth weight, clinical characteristics such as frequency of intraventricular hemorrhage and patent ductus arteriosus needing surgical ligation were similar in both groups (p > 0.05). Characteristics of respiratory support and airway milestones were similar in both groups (p > 0.05). However, infants in NCPAP-oral fed group had earlier acquisition of full oral feeding milestone by 17 days (median) versus infants who were not orally fed during NCPAP (p < 0.05). Discharge weights and the frequency of gastrostomy tube placement were also similar in both groups (p > 0.05). There were no tracheostomies in either group. There was no incidence of clinically significant aspiration pneumonia in infants during the period of the oral feeding while on NCPAP. Controlled introduction of oral feedings in infants with BPD during NCPAP is safe and may accelerate the acquisition of oral feeding milestones.

Autosomal dominant pseudohypoaldosteronism type 1 in an infant with salt wasting crisis associated with urinary tract infection and obstructive uropathy.

Type 1 pseudohypoaldosteronism (PHA1) is a salt wasting syndrome caused by renal resistance to aldosterone. Primary renal PHA1 or autosomal dominant PHA1 is caused by mutations in mineralocorticoids receptor gene (NR3C2), while secondary PHA1 is frequently associated with urinary tract infection (UTI) and/or urinary tract malformations (UTM). We report a 14-day-old male infant presenting with severe hyperkalemia, hyponatremic dehydration, metabolic acidosis, and markedly elevated serum aldosterone level, initially thought to have secondary PHA1 due to the associated UTI and posterior urethral valves. His serum aldosterone remained elevated at 5 months of age, despite resolution of salt wasting symptoms. Chromosomal microarray analysis revealed a deletion of exons 3-5 in NR3C2 in the patient and his asymptomatic mother who also had elevated serum aldosterone level, confirming that he had primary or autosomal dominant PHA1. Our case raises the possibility that some patients with secondary PHA1 attributed to UTI and/or UTM may instead have primary autosomal dominant PHA1, for which genetic testing should be considered to identify the cause, determine future recurrence risk, and possibly prevent the life-threatening salt wasting in a subsequent family member. Future clinical research is needed to investigate the potential overlapping between secondary PHA1 and primary autosomal dominant PHA1.