Long-term teduglutide associated with improved response in pediatric short bowel syndrome-associated intestinal failure.

OBJECTIVES: Patients with short bowel syndrome-associated intestinal failure (SBS-IF) require long-term parenteral nutrition and/or intravenous fluids (PN/IV) to maintain fluid or nutritional balance. We report the long-term safety, efficacy, and predictors of response in pediatric patients with SBS-IF receiving teduglutide over 96 weeks. METHODS: This was a pooled, post hoc analysis of two open-label, long-term extension (LTE) studies (NCT02949362 and NCT02954458) in children with SBS-IF. Endpoints included treatment-emergent adverse events (TEAEs) and clinical response (≥20% reduction in PN/IV volume from baseline). A multivariable linear regression identified predictors of teduglutide response; the dependent variable was mean change in PN/IV volume at each visit over 96 weeks. RESULTS: Overall, 85 patients were analyzed; 78 patients received teduglutide in the parent and/or LTE studies (any teduglutide [TED] group), while seven patients did not receive teduglutide in either the parent or LTE studies. Most TEAEs were moderate or severe in intensity in both groups. By week 96, 82.1% of patients from the any TED group achieved a clinical response, with a mean fluid decrease of 30.1 mL/kg/day and an energy decrease of 21.6 kcal/kg/day. Colon-in-continuity, non-White race, older age at baseline, longer duration of teduglutide exposure, and increasing length of remaining small intestine were significantly associated with a reduction in mean PN/IV volume requirements. CONCLUSIONS: In pediatric patients with SBS-IF, teduglutide treatment resulted in long-term reductions in PN/IV requirements. The degree of PN/IV volume reduction depended on the duration of teduglutide exposure, underlying bowel anatomy, and demographics.

Anastomotic Ulcers: Current Understanding of the Pathogenesis and Management.

PURPOSE OF REVIEW: Anastomotic ulceration following intestinal resection is an under- recognized problem in pediatrics. We discuss the relevant literature regarding this condition. RECENT FINDINGS: Anastomotic Ulceration following intestinal resection is a potentially life threatening cause of refractory anemia. Evaluation should include correction of micronutrient deficiencies and endoscopic evaluation by upper and lower endoscopy and small intestinal endoscopy if necessary. Initial treatment by medical therapy may consist of anti-inflammatory agents as well as antibiotics to treat small intestinal bacterial overgrowth. Surgical resection should be considered if refractory to treatment. Anastomotic ulcers in pediatric patients with small bowel resection should be considered as a cause of refractory iron deficiency anemia. Endoscopic evaluation should be undertaken to look for evidence of anastomotic ulcers. Surgical resection should be considered if medical therapy fails.

Approach to Intestinal Failure in Children.

PURPOSE OF REVIEW: Pediatric intestinal failure is a complex condition requiring specialized care to prevent potential complications. In this article, we review the available evidence supporting recent advances in care for children with intestinal failure. RECENT FINDINGS: Multidisciplinary intestinal rehabilitation teams utilize medical and surgical management techniques to help patients achieve enteral autonomy (EA) while preventing and treating the complications associated with intestinal failure. Recent advances in lipid management strategies, minimization of intestinal failure associated liver disease, prevention of central line-associated blood stream infections, and loss of access, as well as development of promising new hormone analogue therapy have allowed promotion of intestinal adaptation. These advances have decreased the need for intestinal transplant. There have been recent advances in the care of children with intestinal failure decreasing morbidity, mortality, and need for intestinal transplantation. The most promising new therapies involve replacement of enteroendocrine hormones.

Repeat serial transverse enteroplasty procedure (reSTEP): Is it worth it?

BACKGROUND: The utility of repeat serial transverse enteroplasty (reSTEP) has been questioned after patients failed to achieve enteral autonomy. We compared the outcomes after reSTEP to one lifetime STEP (oneSTEP), and tried to identify patients at risk for reSTEP failure. METHODS: All STEPs done at our institution were reviewed. Growth, enteral autonomy, bowel-derived bloodstream infection hospital admissions, complications, and need for bowel transplantation were evaluated (p<0.05 considered significant). RESULTS: 24 patients underwent 32 STEP (16 oneSTEP, 8 reSTEP). reSTEP patients were younger at first surgery (1.01±1.05 vs. oneSTEP 3.06±4.73 years, p = 0.24). Median time to reSTEP was 1.1 year (0.6-5.7). Weight-for-length z-scores improved after reSTEP (0.02±1.40 to 0.22±1.42, p = 0.81). Bowel-derived bloodstream infections decreased after surgery (oneSTEP 1.50±2.25 to 0.94±1.73, p = 0.50; reSTEP 1.88±2.10 to 1.66±2.32, p = 0.52). 37.5% (9/24) patients achieved enteral autonomy at last follow-up: 7/16 oneSTEP, 2/8 reSTEP (p = 0.37). Two complications occurred after oneSTEP (staple line ulcer, leak), none following reSTEP. Three patients (oneSTEP 1/16, reSTEP 2/8, p = 0.19) underwent bowel transplantation (all gastroschisis). CONCLUSION: Similar postoperative outcomes after reSTEP and single STEP (improved enteral tolerance, reduced rates of infections) support the use of reSTEP when clinically indicated, although reSTEP in young infants with a history of gastroschisis may need further evaluation.

Management of Central Venous Access in Children With Intestinal Failure: A Position Paper From the NASPGHAN Intestinal Rehabilitation Special Interest Group.

ABSTRACT: Intestinal failure requires the placement and maintenance of a long-term central venous catheter for the provision of fluids and/or nutrients. Complications associated with this access contribute to significant morbidity and mortality, while the loss of access is an increasingly common reason for intestinal transplant referral. As more emphasis has been placed on the prevention of central line-associated bloodstream infections and new technologies have developed, care for central lines has improved; however, because care has evolved independently in local centers, care of central venous access varies significantly in this vulnerable population. The present position paper from the Intestinal Failure Special Interest Group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) reviews current evidence and provides recommendations for central line management in children with intestinal failure.

Comparison of Aerodigestive and Nonaerodigestive Provider Responses to Clinical Case Vignettes.

OBJECTIVE: To evaluate differences in practice patterns between aerodigestive and nonaerodigestive providers in pediatric gastroenterology when diagnosing and treating common aerodigestive complaints. STUDY DESIGN: A questionnaire comprised of clinical vignettes with multiple-choice questions was distributed to both aerodigestive and nonaerodigestive pediatric gastroenterologists. Vignettes focused on management of commonly encountered general gastroenterology and aerodigestive issues, such as gastroesophageal (GE) reflux, aspiration, and feeding difficulties. Tests of equal proportions were used to compare rates of testing and empiric therapy within and across groups. Multivariate analysis was used to assess differences in response rates between aerodigestive and nonaerodigestive providers. RESULTS: A total of 88 pediatric gastroenterologists from 18 institutions completed the questionnaire. There were 35 aerodigestive gastroenterology providers and 53 nonaerodigestive gastroenterology providers. The nonaerodigestive group included 31 general gastroenterologists and 22 providers with self-identified subspecialty gastroenterology expertise. Aerodigestive specialists were more likely than nonaerodigestive gastroenterologists to pursue testing over empiric therapy in cases involving isolated respiratory symptoms (P < .05); aerodigestive providers were more likely to recommend pH-impedance testing, videofluoroscopic swallow studies, and upper gastrointestinal barium study (P < .05 for each test) depending on the referring physician. For vignettes involving infant GE reflux, both groups chose empiric treatments more frequently than testing (P < .001), although aerodigestive providers were more likely than nonaerodigestive providers to pursue testing like upper gastrointestinal barium studies (P < .05). CONCLUSIONS: Although some practice patterns were similar between groups, aerodigestive providers pursued more testing than nonaerodigestive providers in several clinical scenarios including infants with respiratory symptoms and GE reflux.

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure: Pooled Analysis of 4 Clinical Studies.

BACKGROUND: This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF). METHODS: Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included. RESULTS: Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred. CONCLUSION: Based on integrated data from 4 clinical studies, including long-term follow-up for ≤161 weeks, teduglutide had a safety profile consistent with the individual core pediatric studies and as expected for pediatric patients with SBS-IF who never received teduglutide. The most frequent AEs reflected treatment with teduglutide, complications of the underlying disease, and typical childhood illnesses.

Etiology and Medical Management of Pediatric Intestinal Failure.

Pediatric intestinal failure occurs when gut function is insufficient to meet the growing child's hydration and nutrition needs. After massive bowel resection, the remnant bowel adapts to lost absorptive and digestive capacity through incompletely defined mechanisms newly targeted for pharmacologic augmentation. Management seeks to achieve enteral autonomy and mitigate the development of comorbid disease. Care has improved, most notably related to reductions in blood stream infection and liver disease. The future likely holds expansion of pharmacologic adaptation augmentation, refinement of intestinal tissue engineering techniques, and the development of a learning health network for efficient multicenter study and care improvement.

Utility of liver biopsy in the evaluation of pediatric total parenteral nutrition cholestasis.

BACKGROUND: Cholestasis is a serious complication of total parenteral nutrition (TPN) in neonates. Liver biopsies may be requested to assess the severity of cholestasis and fibrosis. We hypothesized that liver biopsy would not lead to changes in management or improved patient outcomes. METHODS: A single institution retrospective review of infants with TPN cholestasis from January 2008 to January 2016. OUTCOMES: length of stay, complications, change in management and mortality. Statistical analysis was performed using Fisher's exact test. RESULTS: Twenty-seven out of 95 patients with TPN cholestasis underwent liver biopsy. Liver biopsy was associated with increased utilization or ursodeoxycholic acid (p = 0.001). There were no differences in length of stay (LOS) or mortality. One patient had a complication following anesthesia for liver biopsy, there were no bleeding complications recorded. CONCLUSIONS: Liver biopsy in patients with TPN cholestasis was associated with an increase in utilization of ursodeoxycholic acid. The effects of this are not fully understood; however, liver biopsy was not associated with improved patient outcomes such as LOS or mortality.

Intestinal Rehabilitation Programs in the Management of Pediatric Intestinal Failure and Short Bowel Syndrome.

Intestinal failure is a rare, debilitating condition that presents both acute and chronic medical management challenges. The condition is incompatible with life in the absence of the safe application of specialized and individualized medical therapy that includes surgery, medical equipment, nutritional products, and standard nursing care. Intestinal rehabilitation programs are best suited to provide such complex care with the goal of achieving enteral autonomy and oral feeding with or without intestinal transplantation. These programs almost all include pediatric surgeons, pediatric gastroenterologists, specialized nurses, and dietitians; many also include a variety of other medical and allied medical specialists. Intestinal rehabilitation programs provide integrated interdisciplinary care, more discussion of patient management by involved specialists, continuity of care through various treatment interventions, close follow-up of outpatients, improved patient and family education, earlier treatment of complications, and learning from the accumulated patient databases. Quality assurance and research collaboration among centers are also goals of many of these programs. The combined and coordinated talents and skills of multiple types of health care practitioners have the potential to ameliorate the impact of intestinal failure and improve health outcomes and quality of life.

Redefining short bowel syndrome in the 21st century.

In 1968, Wilmore and Dudrick reported an infant sustained by parenteral nutrition (PN) providing a potential for survival for children with significant intestinal resections. Increasing usage of TPN over time led to some patients developing Intestinal Failure Associated Liver Disease (IFALD), a leading cause of death and indication for liver/intestinal transplant. Over time, multidisciplinary teams called Intestinal Rehabilitation Programs (IRPs) began providing meticulous and innovative management. Usage of alternative lipid emulsions and lipid minimization strategies have resulted in the decline of IFALD and an increase in long-term and transplant-free survival, even in the setting of ultrashort bowel (< 20 cm). Autologous bowel reconstructive surgeries, such as the serial tapering enteroplasty procedure, have increased the likelihood of achieving enteral autonomy. Since 2007, the number of pediatric intestinal transplants performed has sharply declined and likely attributed to the newer innovations healthcare. Recent data support the need for changes in the listing criteria for intestinal transplantation given the overall improvement in outcomes. Over the last 50 y, the diagnosis of short bowel syndrome has changed from a death sentence to one of hope with a vast improvement of quality of life and survival.

Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of Teduglutide in Pediatric Short Bowel Syndrome.

OBJECTIVE: To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS-IF). STUDY DESIGN: This 12-week, open-label study enrolled patients aged 1-17 years with SBS-IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used. RESULTS: All patients experienced ≥1 treatment-emergent adverse event; most were mild or moderate. No serious teduglutide-related treatment-emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of -41% and -45%, respectively, with 0.025 mg/kg/d teduglutide and by -25% and -52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and -6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and -1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short-term, open-label design, and small sample size. CONCLUSIONS: Teduglutide was well tolerated in pediatric patients with SBS-IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS-IF. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01952080; EudraCT: 2013-004588-30.

Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection.

Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85α)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of ß-catenin target gene expression, activated caspase-3, survivin, p85α, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85α, and Trp53. At baseline, p85α-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85α, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85α and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome.

Intestinal Anastomotic Ulcers in Children With Short Bowel Syndrome and Anemia Detected by Capsule Endoscopy.

OBJECTIVES: Anastomotic ulcers are a known cause of anemia in children with a history of intestinal resection. Upper endoscopy and colonoscopy can be used to diagnose these ulcers; however, the area of involvement may be difficult to visualize with standard endoscopic techniques. Capsule endoscopy (CE) offers an alternative method for visualizing the small bowel in these patients. We describe a cohort of patients with short bowel syndrome (SBS) and anemia who had anastomotic ulcers detected by CE. METHODS: Retrospective chart review of patients with SBS at our institution who underwent CE for chronic gastrointestinal (GI) blood loss. RESULTS: Four patients who underwent a total of 6 CE procedures were identified. The underlying diagnoses included necrotizing enterocolitis (n = 2), gastroschisis (n = 1), and jejunal atresia (n = 1). All of the patients had their ileocecal valves resected during previous surgeries and had received blood transfusions within the previous several months. The median age at the time of CE was 5.5 years (range 4-14 years). Enterocolonic anastomotic ulcers were noted in the studies as wide, flat circumferential lesions with a white base. The CE results guided a change in medical management in all of the 4 patients, including surgical revision of their anastomosis. CONCLUSIONS: CE may be a helpful adjunctive tool for detecting anastomotic ulcers in patients with SBS and chronic GI blood loss.

Oral risedronate sodium improves bone mineral density in non-ambulatory patients: a randomized, double-blind, placebo controlled trial.

AIMS: Investigate the efficacy of risedronate sodium (Procter and Gamble, Cincinnati, USA) for treating reduced lumbar spine (LS) bone mineral density (BMD) in non-ambulatory patients. METHODS: Nine (10-39 years, mean age 23.0 years, 7 males) in the risedronate arm and 10 (10-35 years, mean age 21.4 years, 8 males) in the placebo arm completed 24 months of therapy at baseline, 6, 12, 18, and 24 months. The primary outcome was change in LS BMD assessed by dual energy x-ray absorptiometry (DXA). Secondary outcomes included changes in serum bone markers, bone specific alkaline phosphatase, osteocalcin, and N-telopeptides. Mixed models examined group, time, and the group by time interaction for the 4 post-baseline time points. RESULTS: The change in LS BMD score from baseline to 24 months was 0.069 (95% CI 0.014 to 0.124) in risedronate participants compared to -0.015 (95% CI -0.073 to 0.042) (t Value = -2.40, P > t=0.03) in the controls. When controlling for baseline scores, the difference was consistent across four post-baseline time points tested (F=5.67, Pr > F=0.03). No differences in serum bone markers were observed. CONCLUSIONS: Risedronate increases LS BMD in non-ambulatory patients with minimal side effects.