Successful Establishment of the First Neonatal Respiratory Extracorporeal Membrane Oxygenation (ECMO) Program in the Middle East, in Collaboration With Pediatric Services.

Background: Extracorporeal membrane oxygenation (ECMO) is a complex life-saving support for acute cardio-respiratory failure, unresponsive to medical treatment. Starting a new ECMO program requires synergizing different aspects of organizational infrastructures and appropriate extensive training of core team members to deliver the care successfully and safely. Objectives: To describe the process of establishing a new neonatal ECMO program and to evaluate the program by benchmarking the ECMO respiratory outcomes and mechanical complications to the well-established Extracorporeal Life Support Organization (ELSO) registry data. Materials and Methods: We reviewed the processes and steps involved in planning and setting up the new ECMO program. To assess the success of the ECMO implementation program, we retrospectively reviewed data of clinical outcomes and technical complications for the first 11 patients who have received ECMO therapy for respiratory indications since program activation (July 2018-May 2020). We analyzed mechanical complications as a tool to measure infrastructures and our effective training for the core team of ECMO specialists. We also looked at all clinical complications and benchmarked these numbers with the last 10 years of ELSO registry data (2009-2019) in the corresponding categories for comparison. Chi-square test was used to compare, and outcomes are presented in percentage; a p-value of <0.05 is considered significant. Results: A total of 27 patients underwent ECMO in the hospital, out of which 11 (six neonatal and five pediatric) patients had acute respiratory failure treated with venovenous (VV) ECMO or veno-arterial (VA) ECMO over a 22-month period. We had a total of 3,360 h of ECMO run with a range from 1 day to 7 weeks on ECMO. Clinical outcomes and mechanical complications are comparable to ELSO registry data (no significant difference); there were no pump failure, oxygenator failure, or pump clots. Conclusions: Establishing the ECMO program involved a multisystem approach with particular attention to the training of ECMO team members. The unified protocols, equipment, and multistep ECMO team training increased staff knowledge, technical skills, and teamwork, allowing the successful development of a neonatal respiratory ECMO program with minimal mechanical complications during ECMO runs, showing a comparable patient flow and mechanical complications.

History of WOFAPS (1963-2019).

The formation of the World Federation of Associations of Pediatric Surgery (WOFAPS) was an important unifying force in the emergence of pediatric surgery as a distinct specialty. Beginning with the formation of several national societies in the early '60s, an early, multinational effort was created. This was in large part fostered by the International Pediatric Association (IPA), which lent logistical support from the medical pediatric community to the pediatric surgeons. In 2001, the mission of the Federation was formalized to focus on the development and education of surgeons serving children, in all parts of the world. This was articulated in the famous Kyoto Declaration of Pediatric Surgery: "Every infant and child who suffers from an illness or disease has the right to be treated in an environment devoted to their care by a pediatric medical or surgical specialist". This vision was unique at the time and foreshadowed the major increase in advocacy activity which has emerged in recent years. While the mission has evolved with time, the present organization continues to hold true to the guiding principles of the original founders and seeks to improve the quality of "Surgical Care for the child, no matter where they live". Education and collaboration across borders underpins the organization's endeavors.

Ileal Transposition in Rats Reduces Energy Intake, Body Weight, and Body Fat Most Efficaciously When Ingesting a High-Protein Diet.

PURPOSE: Ileal transposition (IT) allows exploration of hindgut effects of bariatric procedures in inducing weight loss and reducing adiposity. Here we investigated the role of dietary macronutrient content on IT effects in rats. METHODS: Male Lewis rats consuming one of three isocaloric liquid diets enriched with fat (HF), carbohydrates (HC), or protein (HP) underwent IT or sham surgery. Body weight, energy intake, energy efficiency, body composition, and (meal-induced) changes in plasma GIP, GLP-1, PYY, neurotensin, and insulin levels were measured. RESULTS: Following IT, HC intake remained highest leading to smallest weight loss among dietary groups. IT in HF rats caused high initial weight loss and profound hypophagia, but the rats caught up later, and finally had the highest body fat content among IT rats. HP diet most efficaciously supported IT-induced reduction in body weight and adiposity, but (as opposed to other diet groups) lean mass was also reduced. Energy efficiency decreased immediately after IT irrespective of diet, but normalized later. Energy intake alone explained variation in post-operative weight change by 80%. GLP-1, neurotensin, and PYY were upregulated by IT, particularly during (0-60 min) and following 17-h post-ingestive intake, with marginal diet effects. Thirty-day post-operative cumulative energy intake was negatively correlated to 17-h post-ingestive PYY levels, explaining 47% of its variation. CONCLUSION: Reduction in energy intake underlies IT-induced weight loss, with highest efficacy of the HP diet. PYY, GLP-1, and neurotensin levels are upregulated by IT, of which PYY may be most specifically related to reduced intake and weight loss after IT.

Updating the Surgical Preference List.

Surgical procedure 'preference lists' are used worldwide, but their practice varies widely. Despite being positioned at a critical point in a surgical care pathway, they are often underemphasized, poorly maintained, and substandard. The following editorial material is gleaned from our experience in the set-up of a tertiary hospital on a green field site in Qatar. We comment on the use of preference lists, and contend that focus on standardizing and maintaining preference lists within an electronic record affords substantial opportunities for cost containment, whilst adding efficiency, safety, and value. We believe this approach represents an 'easy win' which would be applicable elsewhere.

The glucagon like peptide-2 'axis': Capacity for production and response following intestinal resection or repair of gastroschisis in infants.

PURPOSE: This study investigates the relationship between the enteric hormone glucagon-like peptide 2 (GLP-2) production, sensitivity, and intestinal adaptation in infants following resection or repair of gastroschisis. METHODS: With IRB approval (UCalgary #10656), consent was obtained from families of infants undergoing surgery for prospective monitoring of nutritional status, GLP-2 levels, and where possible, tissue sampling. RESULTS: Infants who adapted and weaned from parenteral nutrition (PN) had increased GLP-2 (86±32) n=24 vs. controls: 45±20 n=10 and vs. patients on prolonged PN: 42±6 pM, n=10). This was maintained to one year: weaned patients: 72±49 vs. non-weaned: 35±15 pM (p<0.05). Infants with gastroschisis (n=33) had decreased GLP-2 levels until enteral function was achieved and then became elevated: (21±15 with first feeding vs. 102±60 at full feeds and 60±19 pM at one year). There were no changes in the density or distribution of GLP-2 producing L-cells related to gestational age, nor in the expression of the GLP-2 receptor. CONCLUSION: GLP-2 levels correlate with intestinal adaptation in infants, and with recovery of intestinal function in gastroschisis. GLP-2 productive capacity (L-cell expression) and GLP-2 receptor expression do not vary with maturity. The findings support a role for GLP-2 in regulating intestinal function. Further study is suggested.

Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats.

OBJECTIVE: To determine the effects of exogenous glucagon-like peptide-2 (GLP-2), with or without massive distal bowel resection, on adaptation of jejunal mucosa, enteric neurons, gut hormones and tissue reserves in rats. BACKGROUND: GLP-2 is a gut hormone known to be trophic for small bowel mucosa, and to mimic intestinal adaptation in short bowel syndrome (SBS). However, the effects of exogenous GLP-2 and SBS on enteric neurons are unclear. METHODS: Sprague Dawley rats were randomized to four treatments: Transected Bowel (TB) (n = 8), TB + GLP-2 (2.5 nmol/kg/h, n = 8), SBS (n = 5), or SBS + GLP-2 (2.5 nmol/kg/h, n = 9). SBS groups underwent a 60% jejunoileal resection with cecectomy and jejunocolic anastomosis. All rats were maintained on parenteral nutrition for 7 d. Parameters measured included gut morphometry, qPCR for hexose transporter (SGLT-1, GLUT-2, GLUT-5) and GLP-2 receptor mRNA, whole mount immunohistochemistry for neurons (HuC/D, VIP, nNOS), plasma glucose, gut hormones, and body composition. RESULTS: Resection increased the proportion of nNOS immunopositive myenteric neurons, intestinal muscularis propria thickness and crypt cell proliferation, which were not recapitulated by GLP-2 therapy. Exogenous GLP-2 increased jejunal mucosal surface area without affecting enteric VIP or nNOS neuronal immunopositivity, attenuated resection-induced reductions in jejunal hexose transporter abundance (SGLT-1, GLUT-2), increased plasma amylin and decreased peptide YY concentrations. Exogenous GLP-2 attenuated resection-induced increases in blood glucose and body fat loss. CONCLUSIONS: Exogenous GLP-2 stimulates jejunal adaptation independent of enteric neuronal VIP or nNOS changes, and has divergent effects on plasma amylin and peptide YY concentrations. The novel ability of exogenous GLP-2 to modulate resection-induced changes in peripheral glucose and lipid reserves may be important in understanding the whole-body response following intestinal resection, and is worthy of further study.

A safety and pharmacokinetic dosing study of glucagon-like peptide 2 in infants with intestinal failure.

BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF. METHODS: With parental consent (Health Canada Protocol:150,979), parenteral nutrition (PN)-dependent infants were treated with 5-20-µg/kg/day GLP-2 for 3days (phase 1), and if tolerated continued for 42days (phase 2). Nutritional therapy was by primary caregivers, and follow-up was to one year. RESULTS: Six patients were enrolled, age 5.4±3.2months, bowel length: 27±12% of predicted, PN dependent (67±18% of calories). GLP-2 did not affect vital signs, nor were there significant adverse events during the trial. Dosing 5µg/kg/day gave GLP-2 levels of 52-57pmol/L, with no change in half-life or endogenous GLP-2 levels. Enteral feeds, weight, Z scores, stooling frequency, and citrulline levels improved numerically. The trial was discontinued early because of a drop in potency. CONCLUSIONS: GLP-2 was well tolerated in infants, and pK was similar to children with no changes in endogenous GLP-2 release. The findings suggest that GLP-2 ligands may be safely used in infants and may have beneficial effects on nutritional status. Further study is required. LEVEL OF EVIDENCE: 2b Prospective Interventional Study.

Safety and Dosing Study of Glucagon-Like Peptide 2 in Children With Intestinal Failure.

BACKGROUND AND AIMS: A glucagon-like peptide 2 (GLP-2) analogue is approved for adults with intestinal failure, but no studies of GLP-2 have included children. This study examined the pharmacokinetics, safety, and nutritional effects of GLP-2 in children with intestinal failure. METHODS: Native human GLP-2(1-33) was synthesized following good manufacturing practices. In an open-label trial, with parental consent, 7 parenteral nutrition-dependent pediatric patients were treated with subcutaneous GLP-2 (20 µg/kg/d) for 3 days (phase 1) and, if tolerated, continued for 42 days (phase 2). Nutritional treatment was directed by the primary caregivers. Patients were followed to 1 year. RESULTS: Seven patients were enrolled (age: 4.0 ± 0.8 years; bowel length, mean ± SEM: 24% ± 4% of predicted). All were parenteral nutrition dependent since birth, receiving 44% ± 5% of calories by parenteral nutrition. GLP-2 treatment had no effect on vital signs (blood pressure, heart rate, and temperature) and caused no significant adverse events. Peak GLP-2 levels were 380 pM (day 3) and 295 pM (day 42), with no change in half-life or endogenous GLP-2 levels. Nutritional indices showed a numeric improvement in z scores and citrulline levels; the z score was maintained while citrulline levels returned to baseline once GLP-2 was discontinued. CONCLUSIONS: GLP-2 was well tolerated in children, with a pharmacokinetic profile similar to that of adults. There were no changes in endogenous GLP-2 release or metabolism. These results suggest that GLP-2 ligands may be safely used in pediatric patients; larger trials are suggested to investigate nutritional effects.

Preventing the Progression of Intestinal Failure-Associated Liver Disease in Infants Using a Composite Lipid Emulsion: A Pilot Randomized Controlled Trial of SMOFlipid.

BACKGROUND: To examine whether SMOFlipid prevents progression of intestinal failure-associated liver disease (IFALD) in parenteral nutrition (PN)-dependent infants with early IFALD (conjugated bilirubin 17-50 µmol/L, 1-3 mg/dL). STUDY DESIGN: Pilot multicenter blinded randomized controlled trial comparing SMOFlipid with Intralipid. Patients received the trial lipid for up to 12 weeks, unless they achieved full enteral tolerance sooner. The primary clinical outcome was the serum conjugated bilirubin. RESULTS: Twenty-four infants (mean age, 6 weeks) participated in the trial (13 Intralipid and 11 SMOFlipid). At the time of trial enrollment, patients in both groups were receiving 90% of their calories by PN. Mean duration on trial was 8 weeks and did not differ according to treatment ( P = .99). At trial conclusion, patients who received SMOFlipid had a lower conjugated bilirubin than those who received Intralipid (mean difference, -59 µmol/L; P = .03). Patients receiving SMOFlipid were also more likely to have a decrease in serum conjugated bilirubin to 0 µmol/L than those in the Intralipid group over the entire observation period (hazard ratio, 10.6; 95%; P = .03). The time to achievement of full enteral tolerance did not differ statistically (hazard ratio, 1.3; P = .59) between the groups. There was no significant difference in safety outcomes between the groups. CONCLUSIONS: Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.

Differential Effects on Intestinal Adaptation Following Exogenous Glucagon-Like Peptide 2 Therapy With and Without Enteral Nutrition in Neonatal Short Bowel Syndrome [Formula: see text].

BACKGROUND: We aim to study the efficacy of exogenously administered glucagon-like peptide 2 (GLP-2) on intestinal adaptation in 2 preclinical models of neonatal short bowel syndrome (SBS) according to remnant intestinal anatomy, with and without ileum. Furthermore, we aim to determine if this adaptive effect was potentiated with enteral nutrition (EN). METHODS: Neonatal piglets were block-randomized to 75% mid-intestinal (JI group, retains ileum) or distal-intestinal (JC group, has no ileum) resection or no resection (sham control) and GLP-2 treatment (11 nmol/kg/d) or saline control for 7 days. Piglets received nutrition support, either 100% parenteral nutrition (PN; 0% EN, n = 32 in total) or 80% PN + 40% EN (n = 28 in total). Adaptation was assessed by morphological and histological changes, as well as RT quantitative polymerase chain reaction of nutrient transporters and tight junctional proteins and fat absorption. Data are analyzed by 3-way analysis of variance (ANOVA) and 2-way ANOVA per EN level. RESULTS: GLP-2 treatment lengthened villi, deepened crypts, and improved intestinal weight in the remnant intestine of JC piglets. EN was a more potent adaptive stimulus for JI piglets. Small intestinal lengthening occurred only in the JI group, when given EN. There was no difference in total fat absorption and messenger RNA expression of nutrient transporters and tight junctional proteins. CONCLUSIONS: GLP-2 administration augmented structural adaptation in JC piglets with distal intestinal resection. Given JI anatomy, further stimulation by GLP-2 treatment over innate adaptation and stimulation by EN was modest and restricted to ileum. The differential effect of GLP-2 in neonatal SBS, depending on remnant anatomy, has important implications for clinical translation and planning of clinical trials.

Robotic-assisted minimally invasive surgery of the spine (RAMISS): a proof-of-concept study using carbon dioxide insufflation for multilevel posterior vertebral exposure via a sub-paraspinal muscle working space.

BACKGROUND: Open posterior spinal procedures involve extensive soft tissue disruption, increased hospital length of stay, and disfiguring scars. Our aim was to demonstrate the feasibility of using robotic-assistance for minimally invasive exposure of the posterolateral spine with and without carbon dioxide (CO2 ) insufflation. METHODS: Sheep specimens underwent minimally invasive subperiosteal dissection of the spine during three trials. The da Vinci S Surgical system was used for access with and without working space support via CO2 insufflation. RESULTS: Without insufflation, a sub-paraspinal muscle tunnel measuring 16 cm was developed between two 5 cm incisions. With insufflation, the one-sided tunnel length was 12.5 cm but without the soft tissue trauma and obstructed visualization experienced without CO2 . CONCLUSIONS: The use of robot-assistance for minimally invasive access to the posterior spine appears to be feasible. The use of CO2 insufflation greatly improved our ability to visualize and access the posterior vertebral elements.

Pathophysiology, prevention, treatment, and outcomes of intestinal failure-associated liver disease.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) remains a serious problem in the treatment of infants with nutritional problems and short bowel syndrome. METHODS: A review of the recent literature from 2010 to 2016, concentrating on articles related to the pathophysiology of IFALD and to outcomes of novel nutritional and pharmacological therapies for neonatal cholestasis in the post-surgical neonate. RESULTS: The pathophysiology of IFALD relates to an increase sensitivity of the neonatal liver to cholestasis in the non-fed state; prolonged cholestasis almost inevitably results in liver damage which will progress from fibrosis to cirrhosis. Clinically discerned risk factors include premature birth, inflammation, sepsis, disruption of the enterohepatic circulation by creation of a proximal stoma, and the duration and type of parenteral nutritional support. Within the hepatocyte, the regulatory enzyme farsanoid receptor X (FXR) appears to play a pivotal role in the development of cholestasis. Recent studies have shown that its activity is suppressed by sepsis, and by plant phytosterols found in soy-based lipid preparations. This paradigm is reflected in the emerging consensus for the care of post-surgical neonates, which is based around a multi-disciplinary team approach. Using an algorithm-driven approach, an appropriate balance between caloric support and prevention of IFALD can be achieved. CONCLUSIONS: Further prospective studies are required to further refine the optimal sequence of use of these therapies and the long-term effects on neurological development and hepatic function. However, with optimal care, the number of IF patients progressing to end-stage liver disease because of IFALD should be very low.

Glucagon-Like Peptide-2 Alters Bile Acid Metabolism in Parenteral Nutrition--Associated Liver Disease.

BACKGROUND: We aim to study the mechanisms underlying our previous finding that exogenous glucagon-like peptide-2 (GLP-2) treatment in a preclinical model of neonatal parenteral nutrition-associated liver disease (PNALD) improves cholestasis. METHODS: Neonatal piglets received 17 days of parenteral nutrition (PN) therapy and either saline control (PN/Saline n = 8) or GLP-2 treatment at 11 nmol/kg/d (PN/GLP-2, n = 7). At terminal laparotomy, bile and liver samples were collected. The relative gene expression of enzymes involved in bile acid synthesis, regulation, and transport was measured in liver by reverse-transcriptase quantitative polymerase chain reaction. Bile acid composition in bile was determined using tandem mass spectrometry. Data were analyzed using 1-way analysis of variance (ANOVA) or Kruskal-Wallis ANOVA. RESULTS: GLP-2 increased the expression of bile acid export genes: multidrug resistance-associated proteins 2 (MRP2) (P = .002) and 3 (MRP3) (P = .037) over saline control. GLP-2 increased expression of Farnesoid X receptor (FXR) (P < .001) and CYP7A1 (cytochrome P450, family 7, subfamily A, polypeptide 1) (P = .03). GLP-2 treatment was associated with decreased concentrations of taurohyocholic acid and conjugates of toxic lithocholic acid (P < .01). GLP-2 treatment increased the liver bile acid content. CONCLUSIONS: GLP-2 treatment was associated with alterations in the hepatic expression of genes involved in bile acid metabolism. The transcriptomic results indicate the mechanisms at the transcriptional level acting to regulate bile acid synthesis and increase bile acid export. Differences in bile acid profiles further support a beneficial role for GLP-2 therapy in PNALD.

Glucagon-Like Peptide 2 Improves Cholestasis in Parenteral Nutrition--Associated Liver Disease.

BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) remains a significant cause of morbidity and mortality in neonates with intestinal failure. Although glucagon-like peptide-2 (GLP-2) is being advanced as therapy, the effect of GLP-2 treatment on PNALD is unknown. We aim to investigate the effect of exogenous GLP-2 administration on hepatic function in a neonatal piglet model of PNALD. METHODS: Neonatal piglets (aged 2-6 days) underwent jugular venous catheterization to receive isonitrogenous, isocaloric parenteral nutrition (PN). Piglets were allocated to 2 groups: group 1 (n = 8) received saline while group 2 (n = 7) received GLP-2 (at 11 nmol/kg/d). After 17 days, piglets underwent terminal laparotomy, and bile flow was measured. Liver specimens were analyzed histologically and with immunoperoxidase staining. Age-matched sow-reared control piglets (group 3, n = 8) were used for comparison. RESULTS: Both groups 1 and 2 receiving PN developed cholestasis relative to sow-reared controls, as evidenced by a decrease in bile flow and increase in serum total bilirubin. However, group 2 had improved bile flow (1.35 vs 0.73 µL/g; P = .02) and diminished bilirubin (38.0 vs 78.5 µmol/L; P = .008) compared with group 1. Group 2 also had lower serum alanine aminotransferase levels, a marker of liver injury. Histologically, the liver specimens in group 1 had marked hepatocyte pigmentation, which was decreased in group 2 specimens. CONCLUSIONS: The exogenous administration of GLP-2 is associated with the improvement of cholestasis and liver injury. This study introduces a novel role for GLP-2 in improving PNALD in the setting of prolonged PN duration.

Prematurity Reduces Functional Adaptation to Intestinal Resection in Piglets.

BACKGROUND: Necrotizing enterocolitis and congenital gastrointestinal malformations in infants often require intestinal resection, with a subsequent risk of short bowel syndrome (SBS). We hypothesized that immediate intestinal adaptation following resection of the distal intestine with placement of a jejunostomy differs between preterm and term neonates. METHODS: Preterm or term piglets were born by cesarean section and fed enterally for 2 days. On day 2, piglets were subjected to 50% distal intestinal resection with placement of a jejunostomy. On the following 4-5 days, piglets received parenteral nutrition with gradually increasing doses of enteral nutrition (bovine colostrum). Intestinal tissue samples were collected at delivery and 2 and 6-7 days after birth for histological examination and assessment of digestive enzyme activities. RESULTS: Preterm and term piglets showed similar increases in intestinal weight and digestive enzyme activities from birth to 2 days. On days 6-7 after birth, the remnant intestine showed a similar density (g/cm) and mucosal mass in term and preterm piglets, but villus height, crypt depth, enzyme activities (sucrase, maltase, dipeptidyl peptidase IV [DPPIV]), and hexose uptake capacity were significantly higher in term piglets (P < .05). Preterm piglets were more prone to develop hypoglycemia, respiratory distress syndrome, dehydration, and circulatory instability after surgery compared with term piglets. CONCLUSION: Studies on intestinal adaptation after resection are feasible in both preterm and term piglets, but intensive clinical support is required when rearing preterm piglets with SBS. Physiological instability and immaturity of the intestine may explain the fact that immediate adaptation after resection is reduced in preterm vs term neonates.

Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges.

Intestinal failure (IF), due to short bowel syndrome (SBS), results from surgical resection of a major portion of the intestine, leading to reduced nutrient absorption and need for parenteral nutrition (PN). The incidence is highest in infants and relates to preterm birth, necrotizing enterocolitis, atresia, gastroschisis, volvulus, and aganglionosis. Patient outcomes have improved, but there is a need to develop new therapies for SBS and to understand intestinal adaptation after different diseases, resection types, and nutritional and pharmacological interventions. Animal studies are needed to carefully evaluate the cellular mechanisms, safety, and translational relevance of new procedures. Distal intestinal resection, without a functioning colon, results in the most severe complications and adaptation may depend on the age at resection (preterm, term, young, adult). Clinically relevant therapies have recently been suggested from studies in preterm and term PN-dependent SBS piglets, with or without a functional colon. Studies in rats and mice have specifically addressed the fundamental physiological processes underlying adaptation at the cellular level, such as regulation of mucosal proliferation, apoptosis, transport, and digestive enzyme expression, and easily allow exogenous or genetic manipulation of growth factors and their receptors (e.g., glucagon-like peptide 2, growth hormone, insulin-like growth factor 1, epidermal growth factor, keratinocyte growth factor). The greater size of rats, and especially young pigs, is an advantage for testing surgical procedures and nutritional interventions (e.g., PN, milk diets, long-/short-chain lipids, pre- and probiotics). Conversely, newborn pigs (preterm or term) and weanling rats provide better insights into the developmental aspects of treatment for SBS in infants owing to their immature intestines. The review shows that a balance among practical, economical, experimental, and ethical constraints will determine the choice of SBS model for each clinical or basic research question.

Exogenous glucagon-like peptide-2 improves outcomes of intestinal adaptation in a distal-intestinal resection neonatal piglet model of short bowel syndrome.

BACKGROUND: Endogenous glucagon-like peptide-2 (GLP-2) levels and intestinal adaptation are reduced in distal-intestinal resection animal models of short bowel syndrome (SBS) that lack remnant ileum. We hypothesized that exogenous GLP-2 would improve intestinal adaptation in a distal-intestinal resection neonatal piglet model of SBS. METHODS: In all, 35 piglets were randomized to 2 treatment and 3 surgical groups: control (sham), 75% mid-intestinal resection (JI), and 75% distal-intestinal resection (JC). Parenteral nutrition (PN) commenced on day 1 and was weaned as enteral nutrition (EN) advanced. IV GLP-2 (11 nmol/kg/d) or saline was initiated on day 2. Piglets were maintained for 14 d. Clinical, functional, morphological, and histological outcomes were obtained. RESULTS: JC-GLP-2 piglets had fewer days on PN (10.0 ± 0.6 vs. 13.8 ± 0.2), more days on EN (4.0 ± 0.6 vs. 0.2 ± 0.2), a higher percentage of EN at termination (92 ± 5 vs. 52 ± 10%), fewer days of diarrhea (8.0 ± 0.7 vs. 12.3 ± 0.4), increased intestinal length (19 ± 4 vs. -5 ± 3%), and deeper jejunal crypts (248 ± 21 vs. 172 ± 12 µm), compared with saline piglets. CONCLUSION: GLP-2 therapy improves clinical, morphological, and histological outcomes of intestinal adaptation in a distal-intestinal resection model of SBS. Since this anatomical subtype represents the majority of clinical cases of neonatal SBS, these results support a potential role for GLP-2 therapy in pediatric SBS.

Rising post-colectomy complications in children with ulcerative colitis despite stable colectomy rates in United States.

BACKGROUND AND AIMS: In children with ulcerative colitis, data on temporal colectomy trends and in-hospital post-colectomy complications are limited. Thus, we evaluated time trends in colectomy rates and post-colectomy complications in children with ulcerative colitis. METHODS: We identified all children (≤18years) with a diagnosis code of ulcerative colitis (ICD-9: 556.X) and a procedure code of colectomy (ICD-9: 45.8 and 45.7) in the Kids' Inpatient Database for 1997, 2000, 2003, 2006 and 2009. The incidence of colectomies for pediatric ulcerative colitis was calculated and Poisson regression analysis was performed to evaluate the change in colectomy rates. In-hospital postoperative complication rates were assessed and predictors for postoperative complications were evaluated using multivariate logistic regression. RESULTS: The annual colectomy rate in pediatric ulcerative colitis was 0.43 per 100,000person-years, which was stable throughout the study period (P>.05). Postoperative complications were experienced in 25%, with gastrointestinal (13%) and infectious (9.3%) being the most common. Postoperative complication rates increased significantly by an annual rate of 1.1% from 1997 to 2009 (P=.01). However, other independent predictors of postoperative complications were not identified. Patients with postoperative complications had significantly longer median length of stay (14.3days vs 8.2days; P<.001) and higher median hospital charges per patient (US $81,567 vs US $55,461; P<.001) compared to those without complications. CONCLUSION: Colectomy rates across the United States in children with ulcerative colitis have remained stable between 1997 and 2009; however, in-hospital postoperative complication rates have increased.

Intestinal muscularis propria increases in thickness with corrected gestational age and is focally attenuated in patients with isolated intestinal perforations.

PURPOSE: Intestinal perforations are common in premature infants, leading to a diagnostic dilemma between necrotizing enterocolitis and isolated intestinal perforation (IIP). IIP is thought to result from a congenital or acquired absence of the muscularis propria. However, developmental events leading to IIP are not well understood. This study examines the relationship between corrected gestational age (CGA) and intestinal muscle development in controls and patients with IIP. METHODS: Specimens from stillbirths and infants undergoing intestinal surgery from 8 to 48weeks' CGA were collected from 2005 to 2012. Twelve patients with IIP were identified. Control specimens were collected during 25 fetal autopsies and 39 bowel resections. In each case, three sections of intestine were examined histologically for muscularis mucosa, circular and longitudinal muscle thickness. Comparisons of control and perforated specimens were performed via linear regression and ANOVA. RESULTS: Controls and adjacent normal segments in IIP showed a linear relationship between thickness of circular and longitudinal muscles with CGA. Circular and longitudinal muscles were thinner in perforated segments than in adjacent normals and CGA-matched controls (p<0.05). CONCLUSION: Intestinal muscularis propria increases in thickness with CGA. Muscle thickness is focally attenuated in patients with isolated intestinal perforations, while the remaining intestine is normal, suggesting that primary repair is an appropriate treatment.

Effects of chronic glucagon-like peptide-2 therapy during weaning in neonatal pigs.

BACKGROUND: The enteroendocrine hormone glucagon like peptide-2 (GLP-2) and its ligands are under development as therapeutic agents for a variety of intestinal pathologies. A number of these conditions occur in neonates and infants, and thus a detailed understanding of the effects of GLP-2 during the phase of rapid growth during infancy is required to guide the development of therapeutic applications. We studied the effects of GLP-2 in the neonatal pig to determine the potential effects of exogenous administration. METHODS: Two day old newborn domestic piglets were treated with GLP-2 (1-33) at 40 µg/kg/day or control drug vehicle (saline), by subcutaneous injection, given in two doses per day, (n=6/group) for 42 days. Animals were weaned normally, over days 21-25. In the fifth week of life, they underwent neuro-developmental testing, and a pharmacokinetic study. On day 42, they were euthanized, and a complete necropsy performed, with histological assessment of tissues from all major organs. RESULTS: GLP-2 treatment was well tolerated, one control animal died from unrelated causes. There were no effects of GLP-2 on weight gain, feed intake, or behavior. In the treated animals, GLP-2 levels were significantly elevated at 2400±600 pM while at necropsy, organ weights and histology were not affected except in the intestine, where the villus height in the small intestine and the crypt depth, throughout the small intestine and colon, were increased. Similarly, the rate of crypt cell proliferation (Ki-67 staining) was increased in the GLP-2 treated animals and the rate of apoptosis (Caspase-3) was decreased, the depth of the microvilli was increased and the expression of the mRNA for the GLP-2 receptor was decreased throughout the small and large intestine. CONCLUSIONS: In these growing animals, exogenous GLP-2 at pharmacologic doses was well tolerated, with effects confined to the gastrointestinal tract.