Faculty Bibliography

BACKGROUND:Few reports explore the frequency and factors associated with diagnostic ultrasound (US) for midgut volvulus. OBJECTIVE:To evaluate predictive factors for diagnostic US for midgut volvulus and clinical outcomes of patients with non-diagnostic US. MATERIALS AND METHODS/METHODS:This retrospective study included infants imaged for midgut volvulus with US. Exams were rated as diagnostic (midgut volvulus present or absent) or non-diagnostic by a pediatric radiologist, and in cases of disagreement with the original report, an additional pediatric radiologist was the tie-breaker. For each exam, the following were recorded: age, weight, respiratory support, exam indication, sonographer experience, and gaseous dilated bowel loops on radiography. Logistic regression models with "stepwise" variable selection were used to investigate the association of diagnostic US for midgut volvulus with each of the independent variables. RESULTS:One hundred nineteen patients were imaged. US was diagnostic in 74% (88/119) of patients. In subsets of patients presenting with bilious emesis or age <28 days, US was diagnostic in 92% (22/24) and 90% (53/59), respectively. Logistic regression suggested that symptom type (bilious vs other) was the best predictor of diagnostic US (type 3 P=0.02). Out of 26 patients with available radiographs, US was diagnostic in 92% (12/13) of patients without bowel dilation on radiographs compared to 62% (8/13) of patients with bowel dilation (P=0.16). Weight, respiratory support, and sonographer experience did not differ between groups. Two sick neonates, ages 2 days and 30 days, in whom the primary clinical concern was dropping hematocrit and sepsis, respectively, had non-diagnostic ultrasounds in the setting of bowel dilation on radiography. Both were found to have midgut volvulus at surgery and both expired. CONCLUSION/CONCLUSIONS:US was most frequently diagnostic in patients with bilious emesis or age less than 28 days. Non-diagnostic US for midgut volvulus must prompt a predetermined follow-up strategy, such as an additional imaging study (e.g., upper GI series), particularly in a sick child, as non-diagnostic US may miss midgut volvulus.

Choledochal cysts are rare cystic dilations of the biliary tree that typically involve the extrahepatic bile duct and more infrequently, the intrahepatic bile ducts. Todani's classification of choledochal cysts is the most referenced system in which five types of choledochal cysts are described. Several new variants have been reported including dilations of the cystic duct and a double common bile duct. We describe a never reported variant involving dilation of the common bile duct, dilation of the cystic duct and an accessory right hepatic duct.

BACKGROUND:Anorectal malformations (ARMs) have a wide spectrum of presentation ranging from mild defects with perineal fistulas to more severe defects requiring complex management. A primary repair of ARMs with perineal or rectovestibular fistulas has been shown to have good outcomes. However, the timing of the reconstruction is still debated. The aim of this study is to investigate the safety of early versus delayed repair. METHODS:This study was performed using data from the National Surgical Quality Improvement Program-Pediatric (NSQIP-P) from 2012 to 2017. Patients who underwent repair of anorectal malformation with perineal or vestibular fistula were included in the study. Patients with associated diagnosis for Hirschsprung disease, cloaca, rectal prolapse or stenosis, bladder exstrophy, and tracheoesophageal fistula were excluded. 30-day postoperative outcomes included wound and nonwound complications, readmissions, and reoperations. Outcomes were compared by early (≤7 days of age) versus delayed repair (6 weeks to 8 months). RESULTS:A total of 291 patients were included, with 66 in the early and 231 in the delayed group. Patients in the early group were more likely to be male (68.2% vs 31.8%; p < 0.01) and have cardiac risk factors (71.2% vs 49.4%, p < 0.01). The mean operative time was significantly shorter in the early group (90.1 vs 129.6 min; p < 0.01). 30-day complications were not statistically significant between the two groups (p = 0.76). After multivariate analysis, timing of repair did not affect 30-day complications (p = 0.15). CONCLUSION/CONCLUSIONS:Our study shows that early repair of low anorectal malformations with a perineal or vestibular fistula appears to be associated with no increase in risk of postoperative complications as compared to delayed repair. At present, the decision remains dependent on the surgeon's experience and judgment. LEVEL OF EVIDENCE/METHODS:Level III. Retrospective comparative study.

BACKGROUND:Opioid misuse continues to be a major source of morbidity and mortality in the US, in both the adult and pediatric populations. Post-operative opioid prescriptions are often the first exposure children have to opioids and increases their risk of chronic use. There is significant variation in the number of opioids following identical procedures and measures have been taken within the adult population to limit this. However, specific post-operative opioid prescription guidelines are not present in the pediatric population. METHODS:Seven common pediatric surgery procedures were selected for inclusion. The recommended number of opioid doses following each procedure was determined by a multi-disciplinary expert panel. All surgery residents were sent an initial survey to determine the number of opioids they would prescribe for each procedure. They were then shown the guidelines and the survey repeated to determine changes in response. RESULTS:35 and 27 general surgery residents took part in and pre- and post-educational surveys respectively. In all procedures, there was a decrease in the mean number of post-operative opioids prescribed. In addition, there was an increase in the number of residents who prescribed within the guidelines and a decrease in the number who overprescribed post-operative opioids. CONCLUSION/CONCLUSIONS:Pediatric postoperative opioid prescribing guidelines derived from expert opinion increase resident compliance with appropriate dosing; this has the potential to decrease the classic problem of general surgery residents accustomed to treating adults overprescribing opioids to children. These results are promising, and we aim to expand on this work and incorporate these guidelines into our clinical practice. LEVEL OF EVIDENCE/METHODS:III/IV.

IMPACT STATEMENT:This study is significant because it demonstrates an attempt to design a scaffold specifically for small intestine using a novel fabrication method, resulting in an architecture that resembles intestinal villi. In addition, we use the versatile polymer poly(glycerol sebacate) (PGS) for artificial intestine, which has tunable mechanical and degradation properties that can be harnessed for further fine-tuning of scaffold design. Moreover, the utilization of PGS allows for future development of growth factor and drug delivery from the scaffolds to promote artificial intestine formation.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.

Short bowel syndrome (SBS) is a major cause of morbidity and mortality in the pediatric population, for which treatment options are limited. To develop novel approaches for the treatment of SBS, we now focus on the development of a tissue-engineered intestine (also known as an "artificial intestine"), in which intestinal stem cells are cultured onto an absorbable bioscaffold, followed by implantation into the host. To enhance the translational potential of these preclinical studies, we have developed three clinically relevant models in neonatal piglets, which approximate the size of the human infant and were evaluated after implantation and establishment of intestinal continuity over the long term. The models included (1) a staged, multioperation approach; (2) a single operation with a de-functionalized loop of small intestine; and (3) a single operation with an intestinal bypass. The first model had complications related to multiple operations in a short time period, including surgical site infections and wound hernias. The second model avoided wound complications, but was associated with high ostomy output, local skin breakdown, and systemic dehydration with associated electrolyte imbalances. The third model was the most effective, although resulted in stoma prolapse. In summary, we have now developed and evaluated three operative methods for the long-term evaluation of the artificial intestine in the piglet, and conclude that a single operation with a de-functionalized loop of small intestine may be an optimal approach for evaluation over the long term.

Short bowel syndrome is a major cause of morbidity and mortality in children. Despite decades of experience in the management of short bowel syndrome, current therapy is primarily supportive. Definitive treatment often requires intestinal transplantation, which is associated with significant morbidity and mortality. In order to develop novel approaches to the treatment of short bowel syndrome, we and others have focused on the development of an artificial intestine, by placing intestinal stem cells on a bioscaffold that has an absorptive surface resembling native intestine, and taking advantage of neovascularization to develop a blood supply. This review will explore recent advances in biomaterials, vascularization, and progress toward development of a functional epithelium and mesenchymal niche, highlighting both success and ongoing challenges in the field.

Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of the premature infant. We have recently shown that NEC development occurs after an increase in proinflammatory CD4Th17 (Th17) cells and reduced anti-inflammatory forkhead box P3 regulatory T cells (Tregs) to the premature small intestine of mice and humans, which can be experimentally reversed in mice by administration of all-trans retinoic acid (ATRA). We have also shown that NEC is characterized by apoptosis of Lgr5-positive intestinal stem cells (ISCs-Lgr5 cells) within the crypts of Lieberkühn, which are subsequently essential for intestinal homeostasis. We now hypothesize that the normal lymphocyte balance within the lamina propria of the intestine can be achieved via administration of ATRA which restores mucosal integrity by preventing the loss of ISCs. Using both in vivo and in vitro strategies, we now demonstrate that Th17 recruitment and Treg depletion lead to increased apoptosis within ISC niches, significantly impairing proliferative capacity and mucosal healing. ATRA exerted its protective effects by preventing T cell imbalance, ultimately leading to the protection of the ISC pool preventing the development of NEC in mice. These findings raise the exciting possibility that dietary manipulations could prevent and treat NEC by modulating lymphocyte balance and the ISC pool within the newborn small intestine.

Necrotising enterocolitis (NEC) is a common disease in premature infants characterised by intestinal ischaemia and necrosis. The only effective preventative strategy against NEC is the administration of breast milk, although the protective mechanisms remain unknown. We hypothesise that an abundant human milk oligosaccharide (HMO) in breast milk, 2'-fucosyllactose (2'FL), protects against NEC by enhancing intestinal mucosal blood flow, and we sought to determine the mechanisms underlying this protection. Administration of HMO-2'FL protected against NEC in neonatal wild-type mice, resulted in a decrease in pro-inflammatory markers and preserved the small intestinal mucosal architecture. These protective effects occurred via restoration of intestinal perfusion through up-regulation of the vasodilatory molecule endothelial nitric oxide synthase (eNOS), as administration of HMO-2'FL to eNOS-deficient mice or to mice that received eNOS inhibitors did not protect against NEC, and by 16S analysis HMO-2'FL affected the microbiota of the neonatal mouse gut, although these changes do not seem to be the primary mechanism of protection. Induction of eNOS by HMO-2'FL was also observed in cultured endothelial cells, providing a link between eNOS and HMO in the endothelium. These data demonstrate that HMO-2'FL protects against NEC in part through maintaining mesenteric perfusion via increased eNOS expression, and suggest that the 2'FL found in human milk may be mediating some of the protective benefits of breast milk in the clinical setting against NEC.