A Novel Phenotype of Calvarial Thickening and Increased Rates of Premature Calvarial Suture Closure in Children With Chronic Lung Disease.

PURPOSE: The purpose of this study was to characterize a novel type of calvarial thickening and provide objective measurements of skull thickness and calvarial suture morphology in patients with bronchopulmonary dysplasia. METHODS: Infants with severe bronchopulmonary dysplasia who also had undergone computed tomography (CT) scans were identified from the neonatal chronic lung disease program database. Thickness analysis was performed using Materialise Mimics. RESULTS: The chronic lung disease team treated 319 patients during the study interval of which, 58 patients (18.2%) had head CT available. Twenty-eight (48.3%) were found to have calvarial thickening. The rate of premature suture closure in the study population was 36.2% (21 of 58 patients), with 50.0% of affected cohort having evidence of premature suture closure on the first CT scan. Multivariate logistic regression identified 2 risk factors, requiring invasive ventilation at 6 months of age and fraction of inspired oxygen requirement at 6 months of age. Increased head circumference at birth protected against the development of calvarial thickening. CONCLUSIONS: We have described a novel subset of patients with chronic lung disease of prematurity who have calvarial thickening with remarkably high rates of premature closure of cranial sutures. The exact etiology of the association is unknown. In this patient population with radiographic evidence of premature suture closure, operative decision should be made after considering unequivocal evidence of elevated intracranial pressure or dysmorphology and balanced against the risk of the procedure.

Postoperative surveillance and detection of postprandial hypoglycemia after fundoplasty in children.

OBJECTIVE: To evaluate the prevalence of postprandial hypoglycemia (PPH) after fundoplasty after the initiation of a universal postoperative glucose surveillance plan in the neonatal intensive care unit (NICU). STUDY DESIGN: This was a retrospective chart review of children (newborn to 18 years) who underwent fundoplasty at The Children's Hospital of Philadelphia during the 2-year-period after the launch of a surveillance protocol in the NICU and other units. The rate of screening, frequency of PPH (postprandial blood glucose <60 mg/dL [3.3 mmol/L] on 2 occasions), frequency of postprandial hyperglycemia preceding PPH, timing of PPH presentation, and related symptoms were evaluated. RESULTS: A total of 285 children were included (n = 64 in the NICU; n = 221 in other units). Of the children screened in all units, 24.0% showed evidence of PPH, compared with 1.3% of unscreened children. Hyperglycemia preceded PPH in 67.7% (21/31) of all screened children. Within the NICU, most children had PPH within 1 week, but only 53.3% exhibited symptoms of dumping syndrome. CONCLUSIONS: This study supports the use of universal postoperative blood glucose surveillance in identifying PPH in children after fundoplasty. Earlier identification of PPH would lead to earlier treatment and minimize the effects of unidentified hypoglycemic events.

Screening for Metabolic Bone Disease of prematurity.

Metabolic bone disease (MBD) of prematurity remains a significant comorbid condition in preterm, low birth weight infants. As the majority of in utero calcium (Ca) and phosphorus (Phos) accretion occurs during the third trimester, many of these children have inadequate mineral stores and are at risk for deficiencies of Ca and Phos. While fortification of formula has allowed for increased mineral delivery to premature infants, intestinal immaturity prevents optimal absorption. This is compounded by immobilization, delayed establishment of enteral feeds, long term parenteral nutrition and medications that may alter mineral levels. Over time, biochemical changes occur and accompany MBD, with poor bone mineralization during this period increasing the risk for complications such as osteopenia, rickets and fractures. Screening is largely based on risk factors, but despite the 2013 AAP Consensus Statement, there remains significant variation in screening practices across institutions. A combination of laboratory and radiologic testing is often used to diagnose and manage MBD of prematurity, but there exists a lack of consensus on which screening tests and thresholds to use. This is in part related to a lack of normative data and clinical trials for preterm infants, and a result, a lack of evidence-based guidelines on the diagnosis and timing of potential treatment. Biochemical markers, such as serum Phos, alkaline phosphatase (ALP) and parathyroid hormone (PTH), have shown some benefit in the diagnosis of MBD in some studies, but have not always been reproducible. Radiographs may identify different degrees of skeletal changes, but these changes may not be detected until later in MBD development. Other modalities, such as DXA and ultrasound, have also been used, but these may be limited by lack of standards in preterm infants or lack of availability in some centers. Further research, more specifically clinical trials, are needed to determine which combination of tests can detect MBD at its earliest, in order to promote early treatment and prevent short- and long-term complications of MBD.

Postprandial Hypoglycemia in Children after Gastric Surgery: Clinical Characterization and Pathophysiology.

BACKGROUND/AIMS: Dumping syndrome is a common complication in children after fundoplication and other gastric surgeries and is characterized by postprandial hypoglycemia (PPH). Children with PPH have an exaggerated GLP-1 response to a meal with an exaggerated insulin surge and subsequent hypoglycemia. We evaluated the role of GLP-1 in the pathogenesis of PPH by examining the effects of GLP-1 receptor blockade on glucose and insulin response to a meal. METHODS: Six children with known PPH after surgery underwent a mixed meal tolerance test with/without the GLP-1 receptor antagonist exendin-(9-39) using an open-label crossover design. RESULTS: Average nadir plasma glucose concentration was ≥65 mg/dl in all treatment conditions; however, 3 out of the 6 subjects had a nadir plasma glucose <65 mg/dl during vehicle infusion, while only 1 out of the 6 had a nadir plasma glucose <65 mg/dl during infusion of exendin-(9-39). Exendin-(9-39) suppressed postmeal insulin concentrations when compared to vehicle, with a lower peak insulin concentration observed in the children who received 500 pmol/kg/min of exendin-(9-39) (131.3 ± 125.1 pmol/l) compared to children who received 300 pmol/kg/min (231.1 ± 153.4 pmol/l) or vehicle (259.7 ± 120.2 pmol/l). Gastric emptying was not different between groups. CONCLUSION: Our results suggest that the exaggerated insulin response to a meal is at least in part due to the effects of GLP-1 on the pancreatic ß-cell and suggest that GLP-1 receptor antagonists may represent a potential avenue of treatment for children with PPH.

Calcitriol treatment in metabolic bone disease of prematurity with elevated parathyroid hormone: A preliminary study.

OBJECTIVE: To describe the association of calcitriol treatment with the change in parathyroid hormone (PTH) and biochemical markers of bone disease in infants with metabolic bone disease of prematurity (MBD) and secondary hyperparathyroidism. STUDY DESIGN: This retrospective chart review examined serum intact PTH, serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (APA), urine calcium/creatinine (UCa/Cr), and tubular reabsorption of phosphate (TRP) in 32 infants prior to and following calcitriol treatment for MBD with PTH >100 pg/ml. 25-hydroxyvitamin D concentrations were recorded. RESULTS: Following calcitriol treatment, PTH decreased from median (min/max) 220 (115/593) to 25 (3/259) pg/ml, p < 0.001; Ca increased from 9.9 (8.9/10.7) to 10.3 (9.7/11.3) mg/dl, p < 0.001; P increased from 4.3 (2.7/6.4) to 5.4 (2.9/7.4) mg/dl, p = 0.001; and TRP increased from 81 (59/98) to 91.5 (78/98) %, p = 0.03. APA did not differ pre-treatment: 616 (209/1193) vs. post-treatment 485 (196/1229) U/L, p = 0.12. Vitamin D deficiency was not present. Hypercalcemia with hypercalciuria occurred in 3/32 subjects, all normalized after dose reduction. CONCLUSION: Improvements in MBD markers and lack of serious adverse effects suggest calcitriol may be a treatment option in infants with MBD and secondary hyperparathyroidism.

Metabolic bone disease of prematurity.

Metabolic bone disease (MBD) of prematurity remains a significant problem for preterm, chronically ill neonates. The definition and recommendations for screening and treatment of MBD vary in the literature. A recent American Academy of Pediatrics Consensus Statement may help close the gap in institutional variation, but evidence based practice guidelines remain obscure due to lack of normative data and clinical trials for preterm infants. This review highlights mineral homeostasis physiology, current recommendations in screening and monitoring, prevention and treatment strategies, and an added perspective of a bone health team serving a high volume referral neonatal intensive care center.

GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel.

Infants with congenital hyperinsulinism owing to inactivating mutations in the K(ATP) channel (K(ATP)HI) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia. In preclinical studies, we showed that the GLP-1 receptor antagonist exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in SUR-1(-/-) mice. The aim of this study was to examine the effects of exendin-(9-39) on fasting blood glucose in subjects with K(ATP)HI. This was a randomized, open-label, two-period crossover pilot clinical study. Nine subjects with K(ATP)HI received either exendin-(9-39) or vehicle on two different days. The primary outcome was blood glucose; secondary outcomes were insulin, glucagon, and GLP-1. In all subjects, mean nadir blood glucose and glucose area under the curve were significantly increased by exendin-(9-39). Insulin-to-glucose ratios were significantly lower during exendin-(9-39) infusion compared with vehicle. Fasting glucagon and intact GLP-1 were not affected by treatment. In addition, exendin-(9-39) significantly inhibited amino acid-stimulated insulin secretion in pancreatic islets isolated from neonates with K(ATP)HI. Our findings have two important implications: 1) GLP-1 and its receptor play a role in the regulation of fasting glycemia in K(ATP)HI; and 2) the GLP-1 receptor may be a therapeutic target for the treatment of children with K(ATP)HI.