Digital Phenotype Generation and Time to Encounter Closure.

This study evaluates whether implementation of a content expert­developed clinical documentation tool can be beneficial to workflow by reducing time from patient arrival to encounter closure among pediatric patients receiving intestinal rehabilitation.

The First Collective Examination of Immunosuppressive Practices Among American Intestinal Transplant Centers.

Background: Unlike other solid organs, no standardized treatment algorithms exist for intestinal transplantation (ITx). We established a consortium of American ITx centers to evaluate current practices. Methods: All American centers performing ITx during the past 3 y were invited to participate. As a consortium, we generated questions to evaluate and collect data from each institution. The data were compiled and analyzed. Results: Ten centers participated, performing 211 ITx during the past 3 y (range, 3-46; mean 21.1). Induction regimens varied widely. Thymoglobulin was the most common, used in the plurality of patients (85/211; 40.3%), but there was no consensus regimen. Similarly, regimens for the treatment of acute cellular rejection, antibody-mediated rejection, and graft-versus-host disease varied significantly between centers. We also evaluated differences in maintenance immunosuppression protocols, desensitization regimens, mammalian target of rapamycin use, antimetabolite use, and posttransplantation surveillance practices. Maintenance tacrolimus levels, stoma presence, and scoping frequency were not associated with differences in rejection events. Definitive association between treatments and outcomes, including graft and patient survival, was not the intention of this initial collaboration and is prevented by the lack of patient-level data and the presence of confounders. However, we identified trends regarding rejection episodes after various induction strategies that require further investigation in our subsequent collaborations. Conclusions: This initial collaboration reveals the extreme heterogeneity of practices among American ITx centers. Future collaboration will explore patient-level data, stratified by age and transplant type (isolated intestine versus multivisceral), to explore the association between treatment regimens and outcomes.

Central venous catheter safety in pediatric patients with intestinal failure.

Children with intestinal failure (IF) require long-term central venous access to provide life-sustaining parenteral nutrition. Mechanical, thrombotic, and infectious complications are potentially life-threatening and may necessitate central venous catheter (CVC) replacement. Repeated central line replacements may lead to a loss of vascular access sites and increases risk for intestinal transplantation. Children with IF face unique challenges for CVC safety given their young age, altered anatomy, and increased risk of thrombosis and infection. The following review addresses preventative, diagnostic, and treatment strategies for central line safety concerns specific to children with IF as well as recommendations for promoting catheter safety during activities, travel, and emergencies.

Evaluation and Management of Iron Deficiency in Children Undergoing Intestinal Rehabilitation-A Position Paper From the NASPGHAN Intestinal Rehabilitation Special Interest Group.

Iron deficiency (ID) is the most common nutritional deficiency affecting children undergoing intestinal rehabilitation (IR). Patients may be asymptomatic or present with nonspecific symptoms including fatigue, irritability, and dizziness. The diagnosis of ID in this population can be complicated by the coexistence of systemic inflammation or other nutritional deficiencies which may mimic ID. Many routinely available laboratory tests lack specificity and no consensus on screening is available. Success in oral and enteral treatment is impeded by poor tolerance of iron formulations in a population already challenged with intolerance. Newer parenteral iron formulations exhibit excellent safety profiles, but their role in repletion in this population remains unclear. The following report, compiled by a multidisciplinary group of providers caring for children undergoing IR and representing the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Special Interest Group for Intestinal Rehabilitation, seeks to address these challenges. After discussing iron physiology and population-specific pathophysiology, we make recommendations on iron intake, iron status assessment, and evaluation for alternative causes of anemia. We then provide recommendations on iron supplementation and treatment of ID anemia specific to this nutritionally vulnerable population.

Medical and Surgical Aspects of Intestinal Failure in the Child.

Medical and surgical care for children with intestinal failure has evolved so that long-term life expectancy is common even in the setting of the shortest bowel lengths. The long-term administration of parenteral nutrition has become safe with alterations in lipid formulation, and the risk of liver injury has been dramatically reduced. Well-established techniques for bowel lengthening and tapering exist to increase the absorptive capacity of the remnant bowel. These advances allow for ongoing intestinal rehabilitation in the child with the ultimate goal of enteral autonomy while the use of intestinal transplantation in this population has declined in recent years.

Analysis of transition from intravenous iron sucrose to ferric carboxymaltose infusions in pediatric patients with intestinal failure.

BACKGROUND: Iron supplementation is required for pediatric patients with intestinal failure (IF). There is a paucity of literature on optimal iron formulation and outcomes in this patient population that requires ongoing supplementation. The aim of this study was to assess outcomes in pediatric patients with IF receiving iron sucrose (IS) vs ferric carboxymaltose (FCM) iron infusions. METHODS: This was a single-center observational cohort study of pediatric patients with IF requiring ongoing intravenous iron supplementation. Patients were transitioned from IS to FCM as iron therapy. Longitudinal linear mixed-effects models and generalized estimating equations were used to compare outcomes, including hematologic, iron, and growth parameters for 12-month treatment duration on each iron formulation. Adverse effects were descriptively summarized. RESULTS: Twenty-three patients were included. Sixteen received IS and later switched to FCM, five received IS only, and two received FCM only. Most patients' etiology of IF was short bowel syndrome (FCM: 81%, IS: 83%). No differences were seen over time for iron, hematologic, and growth metrics between IS and FCM. The median number of infusions over 12 months for those taking IS was 15 (interquartile range [IQR] = 13-26) and 2 for FCM (IQR = 1-2). Asymptomatic hypophosphatemia was noted in both groups. Similar central line-associated bloodstream infection rates were noted. CONCLUSION: IS and FCM infusions both maintained hematologic and iron parameters with no significant difference noted between the two types of iron, though the number of FCM infusions was significantly less. No significant adverse effects were noted.

Prospective evaluation of the family's health-related quality of life in pediatric intestinal failure.

BACKGROUND: Due to altered nutrition regimens and complex medical needs, pediatric intestinal failure (IF) may have a powerful impact on health-related quality of life (HRQOL). Studies have shown that children with IF experience lower HRQOL. Data on the HRQOL of families of children with IF are lacking. METHODS: We performed a prospective analysis of the HRQOL of families of children with IF in a regional intestinal rehabilitation program from 2011 to 2018. The Pediatric Quality of Life Family Impact Module (FIM) was administered annually to parents. FIM scores were regressed on risk factors using linear mixed-effect models that accounted for repeated surveys within families. RESULTS: A total of 117 families completed 272 surveys. FIM scores increased with patient age across nearly all survey dimensions. Total FIM scores were lower when compared to families of healthy children (median differences = -5, P = .01) and similar to families of chronically ill children. While IF families reported major deficits in the Communication (-11, P < .001) and Worry (-17, P < .001) dimensions, they also reported higher Family Relationship scores (+7, P < .01). On multivariable regression, presence of a major comorbidity and four or more hospital admissions in the prior year were associated with lower family HRQOL (P < .05). Parenteral nutrition dependence was independently associated with lower scores in the Communication (-7, P = .03) and Daily Activities (-10, P = .02) dimensions. CONCLUSION: Families of children with IF experience a decreased HRQOL that may improve with patient age. Intestinal rehabilitation programs should address the HRQOL of families in addition to patients.

Neurogenin-3 Enteric Endocrinopathy: A Rare Case of Pediatric Congenital Diarrhea and Diabetes Mellitus.

Disorders of intestinal enteroendocrine cells (EEC) are a rare cause of congenital diarrhea and diabetes. The gene NEUROG3 is essential in EEC differentiation, and mutations in this gene lead to a paucity of EEC in the intestine and pancreas, often presenting clinically as congenital diarrhea and diabetes mellitus. We present the earliest known diagnosis of NEUROG3-associated enteric endocrinopathy, which was identified on a neonatal diabetes genetic panel sent at 4 weeks of age. Our patient presented with severe diarrhea, malnutrition, electrolyte derangements, and neonatal diabetes. He was started on parenteral nutrition at 3 months of age for nutritional and hydration support and required long-acting insulin for his diabetes. We demonstrate significant reduction in EEC, including cells expressing glucagon-like peptide-1, in intestinal biopsies from our patient, raising the possibility that loss of glucagon-like peptide-1 contributes to NEUROG3-associated diarrhea and diabetes mellitus. This case advances our understanding of the presentation, diagnosis, and management of this rare disease.

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.

Teduglutide for pediatric short bowel syndrome patients.

Introduction: The goal for pediatric short bowel syndrome (SBS) patients is intestinal adaptation. Until recently, the medical management of pediatric SBS has centered on the prevention and treatment of complications in order to allow time for adaptation. Teduglutide, glucagon-like peptide 2 (GLP-2) analog, has recently been approved for use in pediatric SBS patients greater than 1 year of age as a novel agent to augment intestinal adaptation. Areas covered: This article reviews the pharmacology, safety, efficacy, and tolerability of GLP-2 analog teduglutide in pediatric patients greater than 1 year of age. We review all current studies and discuss teduglutide's place in pediatric SBS therapy. Expert opinion: Teduglutide marks the first successful pharmacological intervention that augments the natural process of adaptation safely and effectively in SBS pediatric patients. More studies and further development are needed to optimize its potential in other pediatric patients.

Late graft loss after intestinal transplantation.

PURPOSE OF REVIEW: Despite improvement in short-term outcomes after intestinal transplantation in the last 20 years, long-term rates of graft attrition and patient survival remain unchanged, with worse outcomes compared with other solid organ transplants. This review investigates the multiple causes of late graft loss, including chronic rejection, infection, graft-versus-host disease, posttransplant lymphoproliferative disorder and postsurgical complications. RECENT FINDINGS: New insights into immunology of the intestine and evolution of immunosuppression, as well as review of current persistent causes of late graft loss, shed light on findings that may help improve long-term intestinal allograft survival. SUMMARY: Although intestinal transplantation remains a life-saving intervention with significant advancements since its inception, further understanding of mechanisms of injury is needed to improve long-term outcomes and prevent late intestinal graft loss.

Secondary Anticoagulation Prophylaxis for Catheter-Related Thrombosis in Pediatric Intestinal Failure: Comparison of Short- Vs Long-Term Treatment Protocols.

INTRODUCTION: Catheter-related thrombosis (CRT) is a devastating complication of central venous catheters in children with intestinal failure (IF), but the optimal preventive therapy of CRT is unknown. This study assessed the efficacy and safety of 2 protocols of secondary anticoagulation prophylaxis with low-molecular-weight heparin (LMWH). METHODS: This is a comparative cohort study of children from 2 IF programs who received secondary anticoagulation prophylaxis with LMWH for CRT. The short-term protocol group (N = 13) received therapeutic dosing until thrombus resolution or ≤3 months. In the long-term protocol group (N = 26), prophylactic dosing continued until line removal. Patients underwent routine annual vascular ultrasound and were followed for ≥1 year. The primary outcome was development of secondary thrombosis; post hoc analysis assessed rates of secondary thrombosis at 12 months. RESULTS: Patient demographics were similar between groups. Secondary thrombosis occurred in 8 of 13 (62%) patients in the short-term group and in 9 of 26 (35%) in the long-term protocol group (P = .019) in a median time of 144.5 and 689 days, respectively (P = .01). Secondary thrombosis within 12 months occurred in 7 of 13 (54%, short term) and 2 of 26 (8%, long term) patients (P = .001). Secondary thrombosis was associated with catheter replacements (23.5 vs 5.5 catheters per 1000 catheter days; P = .016) and longer daily parenteral nutrition (PN) infusion (24 vs 15.25 hours; P = .044). Compliance was good (>80% of doses) in 92% of patients. CONCLUSIONS: Long-term secondary anticoagulation prophylaxis with LMWH reduces the incidence of secondary thrombosis and should be considered in children with CRT that require PN for prolonged periods of time.

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.

Mesenteric Plexiform Neurofibroma as a Cause of Weight Loss and Chronic Diarrhea in a Patient with YPEL3 Variant.

Mesenteric plexiform neurofibroma is a subtype of plexiform neurofibroma that involves the mesentery and causes a variety of gastrointestinal complaints. Plexiform neurofibroma is classically found in patients with neurofibromatosis type 1, although genetic contributions to plexiform neurofibroma pathogenesis are heterogeneous. We report the first case of mesenteric plexiform neurofibroma in a patient with a YPEL3 pathogenic variant. This patient presented with growth failure, generalized abdominal pain and chronic diarrhea. She was confirmed to have mesenteric plexiform neurofibroma on histopathology and targeted sequencing on affected tissue confirmed that there were no neurofibromatosis type 1 variants present. Given that this patient's mesenteric plexiform neurofibroma is associated with YPEL3 dysfunction, she is unlikely to benefit from MEK inhibitors, which are the newly approved treatment for inoperable plexiform neurofibroma in patients with neurofibromatosis type 1.

Effect of the COVID-19 Pandemic on Pediatric Intestinal Failure Healthcare Delivery.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has influenced how healthcare is being provided, particularly in patients whose diagnoses require multidisciplinary care, such as pediatric intestinal failure (IF). We sought to ascertain the effects of the COVID-19 pandemic on healthcare delivery for pediatric patients with IF. METHODS: A 20-question survey was administered to members of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Intestinal Rehabilitation (IR) Special Interest Group. Input values were "yes" and "no," along with a free-text response. Following a 10-day open survey period, data were divided into cohorts based on patient population size and disease burden by state. Analysis was then performed using the χ2 test application. RESULTS: Responses from 29 centers were included in analysis. Centers that followed >50 patients on parenteral nutrition (PN) were more likely to have social workers present in telemedicine visits and observed more central line difficulties among families. Centers located in states with <40,000 reported cases of COVID-19 saw patients less frequently and were more likely to withhold changes to PN prescriptions. Additionally, the survey revealed a significant degree of financial hardship and food insecurity among families. CONCLUSION: Many aspects of pediatric IF healthcare delivery have been impacted by the COVID-19 pandemic, both for care providers and caregivers. Despite the availability of telemedicine, IR centers should remain attentive to the global needs of the pediatric IF patient, as well as their families.

Evaluation of SMOFlipid in Pediatric Intestinal-Failure Patients and Its Effects on Essential Fatty Acid Levels.

BACKGROUND: SMOFlipid is a mixed-lipid emulsion approved for adults in the United States as an alternative to soybean oil-based lipid (SO). There are limited data on the use of SMOFlipid in pediatrics and its effect on the fatty acid (FA) profile. Our objective was to characterize changes in FA profile, liver function, and growth in pediatric patients with intestinal failure (IF), following transition from SO or a fish-oil (FO) and SO combination to SMOFlipid. METHODS: A retrospective case series was conducted on pediatric parenteral nutrition-dependent IF patients transitioned to SMOFlipid. Demographics, anthropometrics, labs, and achievement of nutrition goals were assessed. Linear mixed-effect models assessed effects on FA levels and clinical outcomes. RESULTS: One hundred thirty-nine FA panels were collected from 20 patients. Median SMOFlipid dose at study completion was 2 g/kg/d (interquartile range, 1.6-2). During the 1.5 years after SMOFlipid initiation, ω-6 FA increased to physiologic levels, arachidonic acid increased from 298 to 461 nmol/mL (P < .001), and linoleic acid increased from 1172 to 1922 nmol/mL (P < .001). ω-3 FA remained within normal limits. Body mass index z-score and length z-score increased, though no significant changes were found. In addition, no significant changes were found in mead acid, hepatic function, triene-to-tetraene ratio, or triglycerides. CONCLUSION: In 20 pediatric IF patients, SMOFlipid allowed greater ω-6 FA provision while maintaining ω-3 FA, hepatic function, and patient growth. This longitudinal study identified improved FA profile associated with SMOFlipid use in comparison with SO with or without FO.

Organization and outcomes of multidisciplinary intestinal failure teams.

Multidisciplinary intestinal failure programs have played a leading role in the improved outcomes observed in children with intestinal failure over the past two decades. These teams evolved from the world of transplantation and now provide comprehensive care of intestinal failure patients and their families. In addition, they provide the foundation for outcomes research and clinical trials in pediatric intestinal failure. The history and composition of multidisciplinary intestinal failure programs is outlined here with a particular emphasis on long-term patient outcomes as reported from the programs themselves. The care of children with intestinal failure has rapidly evolved over the past two decades. In the contemporary era, children with intestinal failure now have a favorable long-term prognosis, and survival is routinely greater than 90%. The improvement in outcomes in this population is secondary to a variety of advances including safe strategies to deliver chronic parenteral nutrition (PN), innovative bowel lengthening techniques, preservation of vascular access, and prevention of sepsis. However, the underlying driver of these advances in care is widely considered to be the advent of multidisciplinary intestinal failure and rehabilitation programs to manage these patients in a comprehensive fashion.

Resolving Malnutrition With Parenteral Nutrition Before Liver Transplant in Biliary Atresia.

OBJECTIVE: Malnutrition is a common complication of end-stage liver disease (ESLD) associated with poor liver transplant outcomes. Nasogastric feeds are used for nutritional supplementation, but some patients remain malnourished. Parenteral nutrition (PN) can be effective, but has potential complications. The primary objective was to evaluate the effect of PN on anthropometric measures in children with ESLD awaiting liver transplant. Secondary objectives were evaluation of PN-associated complications, liver function tests, pediatric end-stage liver disease scores, waitlist time, and post-transplant length of stay (total and time in the intensive care unit). METHODS: A single-center, retrospective chart review analyzing pediatric patients with ESLD receiving PN who were transplanted during a 6-year period. Data were trended and described over time, as were the relationships between anthropometric data and time receiving PN. RESULTS: A total of 44 patients with ESLD were transplanted between January 2010 and December 2015. Eighteen (41%) received PN before transplant; all had biliary atresia with median age at transplant of 10 months (range, 5-18 months). Mid-upper arm circumference and triceps skinfold thickness showed resolution of malnutrition in 7 patients (39%) with normalization of 1 measure in another 4 patients (22%). Of the remaining, 6 had improved z scores and 1 had worsening malnutrition. No deaths occurred in patients receiving PN. Central line infection rates were 3.8/1000 catheter days with 8 total infections in 6 patients over a total of 2117 catheter days. CONCLUSIONS: Children with ESLD and malnutrition who have failed enteral feeding may benefit from PN to improve and/or resolve malnutrition before liver transplant.

Body composition estimation using skinfolds in children with and without health conditions affecting growth and body composition.

BACKGROUND: Body composition prediction equations using skinfolds are useful alternatives to advanced techniques, but their utility across diverse paediatric populations is unknown. AIM: To evaluate published and new prediction equations across diverse samples of children with health conditions affecting growth and body composition. SUBJECTS AND METHODS: Anthropometric and dual-energy X-ray absorptiometry (DXA) body composition measures were obtained in children with Down syndrome (n = 59), Crohn disease (n = 128), steroid-sensitive nephrotic syndrome (n = 67) and a healthy reference group (n = 835). Published body composition equations were evaluated. New equations were developed for ages 3-21 years using the healthy reference sample and validated in other groups and national survey data. RESULTS: Fat mass (FM), fat-free mass (FFM) and percentage body fat (%BF) from published equations were highly correlated with DXA-derived measures (r = 0.71-0.98), but with poor agreement (mean difference = 2.4 kg, -1.9 kg and 6.3% for FM, FFM and %BF). New equations produced similar correlations (r = 0.85-1.0) with improved agreement for the reference group (0.2 kg, 0.4 kg and 0.0% for FM, FFM and %BF, respectively) and in sub-groups. CONCLUSIONS: New body composition prediction equations show excellent agreement with DXA and improve body composition estimation in healthy children and those with selected conditions affecting growth.

Long-term Outcomes in Intestinal Rehabilitation in Children.

Long-term outcomes for pediatric patients with intestinal failure have significantly improved with advances in management of parenteral nutrition and the associated comorbidities. These changes have been driven by the development of multidisciplinary intestinal rehabilitation teams. Overall survival and transplant-free survival rates have increased while the introduction of new management strategies has decreased complications such as central line infections and intestinal failure associated liver disease. Factors have been identified that aid in prediction of duration of parenteral nutrition and time to enteral autonomy. Close long-term monitoring of growth and early evaluation of development are needed as abnormalities in both areas are common. With the improved survival, an important focus going forward will be the study of and improvement in quality of life for both children with intestinal failure and their families.