Being small for gestational age is not an independent risk factor for mortality in neonates with congenital diaphragmatic hernia: a multicenter study.

BACKGROUND: Congenital diaphragmatic hernia (CDH) accounts for 8% of all major congenital anomalies. Neonates who are small for gestational age (SGA) generally have a poorer prognosis. We sought to identify risk factors and variables associated with outcomes in neonates with CDH who are SGA in comparison to neonates who are appropriate for gestational age (AGA). METHODS: We used the multicenter Diaphragmatic Hernia Research & Exploration Advancing Molecular Science (DHREAMS) study to include neonates enrolled from 2005 to 2019. Chi-squared or Fisher's exact tests were used to compare categorical variables and t tests or Wilcoxon rank sum for continuous variables. Cox model analyzed time to event outcomes and logistic regression analyzed binary outcomes. RESULTS: 589 neonates were examined. Ninety were SGA (15.3%). SGA patients were more likely to be female (p = 0.003), have a left sided CDH (p = 0.05), have additional congenital anomalies and be diagnosed with a genetic syndrome (p < 0.001). On initial single-variable analysis, SGA correlated with higher frequency of death prior to discharge (p < 0.001) and supplemental oxygen requirement at 28 days (p = 0.005). Twice as many SGA patients died before repair (12.2% vs 6.4%, p = 0.04). Using unadjusted Cox model, the risk of death prior to discharge among SGA patients was 1.57 times the risk for AGA patients (p = 0.029). There was no correlation between SGA and need for ECMO, pulmonary hypertensive medication at discharge or oxygen at discharge. After adjusting for confounding variables, SGA no longer correlated with mortality prior to discharge or incidence of unrepaired defects but remained significant for oxygen requirement at 28 days (p = 0.03). CONCLUSION: Infants with CDH who are SGA have worse survival and poorer lung function than AGA infants. However, the outcome of SGA neonates is impacted by other factors including gestational age, genetic syndromes, and particularly congenital anomalies that contribute heavily to their poorer prognosis.

Small bowel resection induces long-term changes in the enteric microbiota of mice.

PURPOSE: The enteric microbiome is known to play a major role in healthy gut homeostasis and several disease states. It may also contribute to both the intestinal recovery and complications that occur in patients with short bowel syndrome. The extent and nature of alterations to the gut microbiota following intestinal resection, however, are not well studied in a controlled setting. The purpose of this investigation is to characterize the effects of massive small bowel resection on the murine enteric microflora. METHODS: Wild-type C57BL6 mice, following a week of acclamation to a liquid rodent diet, underwent either 50% proximal small bowel resection (SBR) or a sham operation. Mice were sacrificed, and enteric contents from the small bowel, cecum, and stool were harvested at 7 and 90 days post-operatively. DNA was isolated, and the V3-V5 regions of the 16s rRNA gene amplified and pyrosequenced on a Roche 454 platform. Sequences were clustered into operation taxonomic units and classified. Communities were then analyzed for diversity and phylogenic composition. RESULTS: In the long-term group, the microbes inhabiting the ileum of mice undergoing SBR and sham operation differed significantly at the genus level (p < 0.001). Small bowel contents collected before and after SBR also differed significantly (p = 0.006). This was driven by an increase in Lactobacillus and decrease in Enterobacteriaceae species in mice undergoing SBR. No difference was seen in the long-term stool or in stool, cecal, or ileal contents in the short-term. No difference in microbial community diversity was found in any group. CONCLUSION: Bowel resection induces long-term changes in the microbial community of the murine ileum, but not at more distal sites of the gastrointestinal tract. The increase in Lactobacillus encountered small bowel of resected mice correlates with limited previous studies. These changes may reflect an adaptive response of the microbiota to maximize energy extraction, but further studies are needed to establish the role played by this altered community.

A pediatric acute wound service: a novel approach in wound management.

INTRODUCTION: In 2001, in response to an overwhelming increase in patient visits for various pediatric abscesses, burns, and other wounds, an ambulatory burn and procedural sedation program (Pediatric Acute Wound Service, or PAWS) was developed to minimize operating room utilization. The purpose of this study is to report our initial 7-year experience with the PAWS program. METHODS: The hospital records of all children managed through PAWS from 2001 to 2007 were reviewed. Outcomes measured include patient demographics, number and location of visits per patient, procedure information, cause of wounds, and reimbursement. chi(2) test and linear regression were performed using GraphPad Prism (GraphPad Software Inc, San Diego, CA). RESULTS: Overall, 7620 children (age 0-18 years) received wound care through PAWS from 2001 to 2007. There were no differences in patient age, race, and sex during this time period. Between 2001 and 2007, the percentage of patients seen as outpatients increased from 51% to 68% (P < .05), and the average number of visits per patient decreased from 3.9 to 2.4 (P = .05). In, 2007, 46% of the children required only 1 visit. In 2007, 74% of the visits were for management of wound and soft tissue infections, compared with only 9% in 2001 (P < .05). The contribution margin of a PAWS visit and total contribution margin in 2007 were $1052 and $4.0 million, respectively. CONCLUSION: The creation of PAWS has allowed for the transition in management of most pediatric skin and soft tissue wounds and infections to an independent ambulatory setting, alleviating the need for operating room resources, while functioning at a profitable cost margin for the hospital.

Bowel resection induced intestinal adaptation: progress from bench to bedside.

Intestinal adaptation after massive short bowel resection (SBR) is characterized structurally by an increase in intestinal wet weight, protein, DNA content, villus height, crypt depth, and absorptive surface area. These structural characteristics are driven by a proliferative stimulus that increases crypt cell division and augments cellular progression along the crypt-villus axis. Functional characteristics of adaptation include an upregulation of NA+/Glucose cotransporters, Na+/H+ exchangers, and other enzymes involved in digestion and absorption. The combination of structural and functional adaptation are physiologic live-saving events that compensate for the sudden loss of digestive and absorptive capacity in the remnant intestine. If intestinal adaptation does not occur or is inadequate, a lifelong dependence on parenteral nutrition will ensue, which ultimately results in devastating cholestatic liver dysfunction. Several mediators are thought to play an influential role in postresection small bowel adaptation, including intraluminal nutrients, gastrointestinal secretions, hormones, growth factors, and other genetic/biochemical factors. A thorough understanding of the mechanisms that drive intestinal adaptation will be essential in the development of novel and innovative therapies that result in saving lives.

Intestinal adaptation: structure, function, and regulation.

After massive small bowel resection (SBR), the remnant intestine undergoes an adaptive process characterized by increases in wet weight, protein and DNA content, villus height and crypt depth, and absorptive surface area. These changes are the result of a proliferative stimulus that increases crypt cell mitosis and augments cellular progression along the villus axis. Functionally, there is upregulation of the Na(+)/glucose cotransporter, Na(+)/H(+) exchanger, and other enzymes involved in intestinal digestion and absorption. These physiologic events are a compensatory response to the sudden loss of digestive and absorptive capacity by the remnant intestine. A major consequence of inadequate intestinal adaptation is lifelong dependence on parenteral nutrition, which results ultimately in cholestatic liver dysfunction. Furthermore, adaptation may be associated with changes in intestinal permeability and an increased risk of bacterial translocation and sepsis. Several mediators thought to be integral to the postresection adaptive response have been proposed, including luminal nutrients, gastrointestinal secretions, and humoral factors. A thorough understanding of intestinal adaptation will be essential in the rational development of new and innovative therapies that amplify this complex but important process.

Usefulness of surveillance cultures in neonatal extracorporeal membrane oxygenation.

Sepsis is difficult to identify in patients treated with extracorporeal membrane oxygenation (ECMO). This study evaluates the usefulness of surveillance cultures obtained during ECMO. We retrospectively reviewed the records of 187 patients from four ECMO centers with birth weights 1,574 to 4,900 gm and gestational ages 33-43 weeks, over a 4 year interval. Most patients had surveillance blood cultures daily, and tracheal aspirates and urine culture every other day. Charts were reviewed for culture results before, during, and for the 7 days after ECMO, and clinical response to the culture results. A total of 2,423 cultures were obtained during 1,487 days of ECMO, of which 155 were positive (6.4%): 13 of 1,370 blood cultures (0.9%), 137 of 850 tracheal aspirate cultures (16%), and 5 of 203 urine cultures (2.3%). After 72 hours, tracheal aspirate cultures became positive with nosocomial organisms in 33 of 131 patients. None of 153 bacterial urine cultures were positive, and only one of 34 viral urine cultures were positive (CMV). We conclude that routine daily blood cultures are not useful in neonatal ECMO. Tracheal aspirate cultures may be helpful in the management of antibiotic therapy in patients on ECMO for more than 5 days. Routine bacterial urine cultures did not provide useful information.

Epithelial permeability is not increased in rats following small bowel resection.

BACKGROUND: Increased intestinal permeability and translocation of bacteria and/or bacterial products may cause infection and liver dysfunction in patients with the short bowel syndrome. In previous studies, serum from mice undergoing small bowel resection (SBR) enhanced growth of cultured rat intestinal epithelial cells (RIEC-6), implicating a role for a serum factor(s) in the enterocyte response to SBR. These experiments tested the hypothesis that epithelial cell permeability is increased following SBR. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent a 75% SBR or sham operation. Intestinal permeability in the remnant ileum was determined by Ussing chambers on Postoperative Day (POD) 3. Additionally, serum was collected on POD 1, 3, and 7 and mesenteric lymph was harvested on POD 3. Once confluent, RIEC-6 cells were incubated for 3 days in media supplemented with 10% fetal bovine serum (FBS; control), 1% FBS, 1% FBS plus 9% Sham serum, or 1% FBS plus 9% SBR serum or exposed to media with varied concentrations of SBR or Sham lymph. Monolayer permeability was determined by measuring the passage of dextran-rhodamine. RESULTS: Intestinal permeability was reduced in rats undergoing SBR. Sham serum-treated monolayers demonstrated the greatest permeability. Incubation with SBR serum reduced permeability to near control media. There were no permeability differences between SBR and Sham lymph-treated monolayers. CONCLUSION: The early adaptive response of the remnant intestine after SBR is associated with reduced permeability. These results suggest an alternative mechanism for the increased bacterial translocation that has been described following SBR.

Hypercalcemia associated with extracorporeal life support in neonates.

BACKGROUND/PURPOSE: Disturbances in calcium homeostasis are common at initiation of extracorporeal life support (ECLS). At the authors' institution many neonates undergoing ECLS have developed hypercalcemia. To determine the frequency of hypercalcemia in neonates during ECLS we performed retrospective chart review of neonates that required ECLS at our neonatal intensive care unit. METHODS: The authors identified 76 consecutive neonates who underwent ECLS before 10 days of age at Cincinnati Children's Hospital Medical Center from July 1, 1991 to June 30, 1996. The hospital charts and ELSO forms were reviewed. Demographic, clinical, and laboratory data for each of the patients were reviewed, both before initiation and during ECLS. Hypercalcemia was defined as total serum calcium concentration of greater than 11 mg/dL (2.74 mmol/L) on at least one occasion beyond the first 24 hours of ECLS. RESULTS: The hospital charts and ELSO forms from 70 patients were available for review. One patient was excluded because he was only on ECLS for 33 hours, and there were no calcium levels obtained after 24 hours of ECLS and until death. Twenty-five (36%) neonates undergoing ECLS had hypercalcemia (serum Ca > 11 mg/dL [2.74 mmol/L]). Hypercalcemia was associated with longer duration of ECLS (hypercalcemia group, 243 +/- 115 hours and normocalcemia group, 139 +/- 64 hours) and greater requirements for platelet transfusions (hypercalcemia group, 538 +/- 282 mL and normocalcemia group, 372 +/- 233 mL). This could not be explained by differences in primary diagnosis, amounts of calcium administered, and acid-base status. CONCLUSIONS: Hypercalcemia was found to be common in neonates that require ECLS and is associated with longer duration of ECLS support. Conservative calcium administration for neonates while on ECLS may be warranted.

Serum from mice after small bowel resection enhances intestinal epithelial cell growth.

BACKGROUND/PURPOSE: The adaptive response of the intestine to massive small bowel resection (SBR) is remarkably complex. An in vitro model of adaptation may facilitate the elucidation of signaling pathways involved in this process. In an effort to establish such a model, the effects of serum from resected mice on cultured intestinal epithelial cells were studied. METHODS: Serum was collected and pooled from male ICR mice 3 days after either 50% SBR or sham operation. Rat intestinal epithelial cells (RIEC-6) were plated at equal density and grown in the presence of 1% fetal bovine serum (FBS), 10% FBS, 1% FBS plus 9% sham serum, or 1% FBS plus 9% SBR serum. Cell number, proliferation, and caspase-3 activity were determined. RESULTS: RIEC-6 cell growth was reduced significantly in 1% FBS or sham serum. SBR serum markedly accelerated cell growth and proliferation when compared with all other groups and significantly suppressed caspase-3 activity. CONCLUSIONS: Massive intestinal resection in mice results in a serum factor that induces intestinal cell growth in vitro. This in vitro model of trophic signaling will permit further detailed investigations into the mechanisms of intestinal adaptation.

cDNA microarray analysis of adapting bowel after intestinal resection.

BACKGROUND/PURPOSE: Studies of the genetic regulation of various physiologic processes have been hampered by methodologies that are limited to the analysis of individual genes. The advent of cDNA microarray technology has permitted the simultaneous screening of numerous genes for alterations in expression. In this study, cDNA microarrays were used to evaluate gene expression changes during the intestinal adaptive response to massive small bowel resection (SBR). METHODS: Male ICR mice (n = 20) underwent either a 50% SBR or sham operation and then were given either orogastric epidermal growth factor (EGF, 50 microg/kg/d) or saline. After 3 days, cDNA microarray analysis was performed on mRNA extracted from the remnant ileum. RESULTS: From over 8,700 different genes, the array identified 27 genes that were altered 2-fold or greater after SBR. Small proline-rich protein 2 (sprr2), the gene with the greatest expression change (4.9-fold), was further upregulated by EGF. This gene has never been characterized in the intestine or described in intestinal adaptation. CONCLUSIONS: cDNA microarray analysis showed enhanced expression of sprr2, a gene not previously known to be involved in the physiology of adaptation after SBR. This technology provides a more rapid and efficient means of dissecting the complex genetic regulation of gut adaptation.

Renal cell carcinoma as a secondary malignancy after treatment of acute promyelocytic leukemia.

Numerous children have been treated successfully for cancer and are surviving into adulthood. As this population has aged, an increasing number of secondary malignancies has emerged. Renal cell carcinoma (RCC) is a rare tumor in childhood and has not been documented previously to occur after treatment of acute promyelocytic leukemia (APL). This report describes the clinical course of APL treated in a child in whom RCC subsequently developed during adolescence approximately 5 years after therapy.

Analysis of intestinal adaptation gene expression by cDNA expression arrays.

BACKGROUND: As a tool for determining gene expression on a genomic scale, cDNA microarrays are a promising new technology that can be applied to the study of complex physiologic processes. The objective of this study was to characterize the expression of individual genes and patterns of gene expression that might provide insight into the mechanism of intestinal adaptation after massive small bowel resection. METHODS: Male ICR mice underwent a 50% proximal small bowel resection (SBR) or sham operation. After 3 days, the remnant ileum was harvested, weighed, and RNA extracted. Changes in gene expression were detected utilizing Clontech Atlas mouse cDNA expression arrays. Some of these changes were confirmed by reverse transcriptase-polymerase chain reactions (RT-PCR) and Northern blots. RESULTS: Analysis of these cDNA arrays revealed changes in the expression of multiple genes, including those involved in cell cycle regulation, apoptosis, DNA synthesis, and transcriptional regulation. The patterns of expression were consistent with the increased cell proliferation and apoptosis observed during intestinal adaptation. A large number of genes not previously associated with intestinal adaptation were identified. CONCLUSIONS: This technology may facilitate the elucidation of the intricate cellular mechanisms underlying intestinal adaptation.

Epidermal growth factor is critical for intestinal adaptation following small bowel resection.

The loss of small intestinal mucosal surface area is a relatively common clinical situation seen in both the pediatric and adult population. The most frequent causes include mesenteric ischemia, trauma, inflammatory bowel disease, necrotizing enterocolitis, and volvulus. Following surgical resection, the remnant intestine compensates or adapts to the loss of native bowel by increasing its absorptive surface area and functional capacity. Unfortunately, many patients fail to adapt adequately, and are relegated to lifelong intravenous nutrition. Research into intestinal adaptation following small bowel resection (SBR) has evolved only recently from the gross and microscopic level to the biochemical and genetic level. As understanding of this process has increased, numerous therapeutic strategies to augment adaptation have been proposed. Epidermal growth factor (EGF) is an endogenous peptide that is secreted into the gastrointestinal tract and able to influence gut ontogeny, as well as mucosal healing. Early studies have demonstrated its ability to augment the adaptive process. Focusing on a murine model of massive intestinal loss, the morphological, structural, biochemical, and genetic changes that occur during the intestinal adaptive process will be reviewed. The role of EGF and its receptor as critical mediators of the adaptive process will be discussed. Additionally, the ability of EGF to augment intestinal proliferation and diminish programmed cell death (apoptosis) following SBR will be examined. Enhancing adaptation in a controlled manner may allow patients to transition off parenteral nutrition to enteral feeding and, thereby, normalize their lifestyle.

Bax is required for increased enterocyte apoptosis after massive small bowel resection.

BACKGROUND: Massive small bowel resection (SBR) increases rates of both enterocyte proliferation and apoptosis. Previous studies have demonstrated increased intestinal expression of proapoptotic bax mRNA and protein, as well as the appearance of an 18-kd bax cleavage product within 12 hours of SBR. This study tested the hypothesis that bax is required for postresection increases in enterocyte apoptosis. METHODS: Male bax-null and C57Bl/6 (control) mice underwent either a 50% proximal SBR or sham operation. After 3 days, the remnant ileum was harvested and weighed. Apoptotic indexes, proliferation indexes, villus heights, and crypt depths were determined. RESULTS: The usual adaptive increases in ileal wet weight, crypt depth, and rate of proliferation occurred in both the control and bax-null mice. Resection significantly increased the rate of apoptosis in the control mice; however, it failed to alter the apoptotic index in the bax-null mice. CONCLUSIONS: Bax is necessary for the increase in apoptosis that occurs after SBR, but its absence has no significant effect on short-term adaptation. These findings suggest that enterocyte proliferation and apoptosis are differentially regulated during intestinal adaptation.

Gastrointestinal duplications.

Gastrointestinal duplications are rare congenital lesions that can develop anywhere along the alimentary tract and may present in the newborn period as an abdominal mass. They are differentiated from other intraabdominal cystic lesions by the presence of a normal gastrointestinal mucosal lining. Multiple theories have been proposed to account for these lesions; however, no single theory adequately explains all the known duplications. They are most frequently single, tubular, or cystic and located on the mesenteric side of the native alimentary tract structure. Symptoms often are related to the location of the duplication; oral and esophageal lesions can create respiratory difficulties, whereas lower gastrointestinal lesions may cause nausea, vomiting, bleeding, perforation, or obstruction. Treatment is resection with care taken to protect the common blood supply of the native structures. Occasionally, a partial resection with mucosal excision is required to preserve intestinal mucosa.

Salivary epidermal growth factor and intestinal adaptation in male and female mice.

Salivary epidermal growth factor (sEGF) levels are increased in male mice after small bowel resection (SBR) and may be important during intestinal adaptation. Since males have greater sEGF than females, the influence of sex on postresection adaptation was tested. Females had lower sEGF; however, sEGF substantially increased in both sexes after a massive (50%) SBR. Adaptive increases in DNA and protein content, villus height, and crypt depth, as well as crypt cell proliferation rates in the remnant ileum, were not different between males and females. Although significant postresection increases in sEGF were identified, EGF mRNA and protein did not change within the submandibular gland. Glandular kallikrein-13 and ileal EGF receptor expression were greater after SBR in female mice. Intestinal adaptation is equivalent in female and male mice after SBR. Despite lower sEGF, females demonstrated increased expression of a kallikrein responsible for sEGF precursor cleavage as well as amplified ileal EGF receptor expression. These results endorse an important differential response between sexes regarding sEGF mobilization and intestinal receptor availability during adaptation.