Search

We describe cases of intestinal failure wherein inpatient admission was critical toward enteral autonomy. We performed a retrospective chart review of 6 children with long-term parenteral nutrition dependence who were weaned from parenteral nutrition after admission. Admissions included feeding and medication titration, interdisciplinary care, and a home parenteral nutrition team consultation., Competing Interests: Declaration of Competing Interest C.D. was supported in part by 2P30 DK040561. M.P. is a consultant for Fresenius Kabi and receive royalties for Omegaven. A.C. is an investigator on the Pediatric Teduglutide Registry sponsored by Takeda. A.C. is an investigator on a 90 day, Phase 3, Open Labeled Exploratory Study of RELiZORB to Evaluate Safety, Tolerability, and Nutrient Absorption in Children with Short Bowel Syndrome who are Dependent on Parenteral Nutrition sponsored by Alcresta., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Selection of central venous catheter (CVC) lock solution impacts catheter mechanical complications and central line-associated bloodstream infections (CLABSIs) in pediatric patients with intestinal failure. Disadvantages of the current clinical standards, heparin and ethanol lock therapy (ELT), led to the discovery of new lock solutions. High-risk pediatric patients with intestinal failure who lost access to ELT during a recent shortage were offered enrollment in a compassionate use trial with 4% tetrasodium EDTA (T-EDTA), a lock solution with antimicrobial, antibiofilm, and antithrombotic properties., Methods: We performed a descriptive cohort study including 14 high-risk pediatric patients with intestinal failure receiving 4% T-EDTA as a daily catheter lock solution. CVC complications were documented (repairs, occlusions, replacements, and CLABSIs). Complication rates on 4% T-EDTA were compared with baseline rates, during which patients were receiving either heparin or ELT (designated as heparin/ELT)., Results: Patients initiated 4% T-EDTA at the time they were enrolled in the compassionate use protocol. Use of 4% T-EDTA resulted in a 50% reduction in CVC complications, compared with baseline rates on heparin/ELT (incidence rate ratio: 0.50; 95% CI, 0.25-1.004; P = 0.051)., Conclusion: In a compassionate use protocol for high-risk pediatric patients with intestinal failure, the use of 4% T-EDTA reduced composite catheter complications, including those leading to emergency department visits, hospital admissions, additional procedures, and mortality. This outcome suggests 4% T-EDTA has benefits over currently available lock solutions., (© 2024 American Society for Parenteral and Enteral Nutrition.)

Patients with intestinal failure who receive long-term parenteral nutrition (PN) often develop intestinal failure-associated liver disease (IFALD). Although there are identified risk factors, the early pathogenesis is poorly understood and treatment options are limited. Here, we perform a transcriptomic analysis of liver tissue in a large animal IFALD model to generate mechanistic insights and identify therapeutic targets. Preterm Yorkshire piglets were provided PN or bottle-fed with sow-milk replacer for 14 days. Compared to bottle-fed controls, piglets receiving PN developed biochemical cholestasis by day of life 15 (total bilirubin 0.2 vs. 2.9 mg/dL, P = 0.01). RNA-Seq of liver tissue was performed. Ingenuity Pathway Analysis identified 747 differentially expressed genes (343 upregulated and 404 downregulated) with an adjusted P < 0.05 and a fold-change of > |1|. Enriched canonical pathways were identified, demonstrating broad activation of inflammatory pathways and inhibition of cell cycle progression. Potential therapeutics including infliximab, glucocorticoids, statins, and obeticholic acid were identified as predicted upstream master regulators that may reverse the PN-induced gene dysregulation. The early driver of IFALD in neonates may be inflammation with an immature liver; identified therapeutics that target the inflammatory response in the liver should be investigated as potential treatments., (© 2024. The Author(s).)

Background: Enteral drug therapy is challenging in short bowel syndrome with intestinal failure (SBS-IF) because of unpredictable absorption. SEFA-6179 is an enterally administered medium-chain fatty acid analogue under development for intestinal failure-associated liver disease. We investigate the pharmacokinetics of two SEFA-6179 formulations in two large-animal models of SBS-IF, including a new pseudojejunostomy model., Methods: Twenty Yucatan minipigs were obtained. Half underwent pre-resection pharmacokinetic study with single-dose SEFA-6179 administration. All minipigs then underwent 90% jejunoileal resection, with either a jejunoileal anastomosis or bypass of the intraperitoneal colon with anastomosis just proximal to the rectum (pseudojejunostomy). On postoperative day 3, a single-dose pharmacokinetic study was performed., Results: Both SBS-IF models were well tolerated. Compared with the jejunoileal anastomosis minipigs, pseudojejunostomy minipigs had a more severe malabsorptive phenotype with weight loss by postoperative day 4 (+0.1 vs -0.9 kg, P = 0.03) and liquid diarrhea (Bristol 5 vs Bristol 7, P = 0.0007). Compared with pre-resection minipigs, both jejunoileal and pseudojejunostomy minipigs had lower total plasma exposure of SEFA-6179 measured by area under the curve (jejunoileal: 37% less, P = 0.049; pseudojejunostomy: 74% less, P = 0.0001). Peak plasma concentration was also lower in the pseudojejunostomy group compared with pre-resection (65% less, P = 0.04), but not lower in the jejunoileal group (P = 0.47)., Conclusion: In two SBS-IF minipig models, SEFA-6179 had substantially decreased absorption compared with pre-resection minipigs. Dose optimization for different intestinal anatomy and function may be required. We describe a new SBS-IF pseudojejunostomy model that may improve the translation of preclinical research to patients with SBS-IF who have enterostomies., (© 2023 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Background & Aims: At least 20%-30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium-chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD., Methods: Preterm Yorkshire piglets were delivered by cesarean section, and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium-chain triglyceride vehicle control or SEFA-6179., Results: Compared to medium-chain triglyceride vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs <0.2 mg/dL, P = .01; total bilirubin: 2.7 vs 0.4 mg/dL, P = .02; gamma glutamyl transferase: 172 vs 30 U/L, P = .01). SEFA-6179 also prevented steatosis (45.6 vs 13.9 mg triglycerides/g liver tissue, P = .009), reduced bile duct proliferation (1.6% vs 0.5% area cytokeratin 7 positive, P = .009), and reduced fibrosis assessed by a masked pathologist (median Ishak score: 3 vs 1, P = 0.007). RNA sequencing of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist)., Conclusions: In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ethanol lock therapy (ELT) decreases central line-associated bloodstream infections; however, the effect on mechanical catheter complications is unclear. In recent years, ELT has become unavailable for many patients, often resulting in high-risk patients switching back to heparin locks. We investigated the impact of ELT on mechanical catheter complications during this period., Methods: We performed a retrospective cohort study of the Boston Children's Hospital intestinal rehabilitation program from January 1, 2018, to December 31, 2020. Pediatric patients with a central venous catheter requiring parenteral support for 3 months were included. The primary outcome was the composite rate of mechanical catheter complications (repairs and replacements)., Results: The pediatric intestinal failure cohort consisted of 122 patients. Forty-four percent received ELT for the entirety of the study period, 29% used only heparin locks, and 27% used ELT and heparin locks at different periods. During ELT use, there was 1.65 times the risk of mechanical catheter complications (composite outcome of repairs and replacements) compared with heparin locks (adjusted incidence rate ratio [aIRR] = 1.65, 95% CI = 1.18-2.31). Current ELT use was associated with 2.3 times the risk of catheter repairs (aIRR = 2.30, 95% CI = 1.36-3.89) but no significant increase in catheter replacement risk (aIRR = 1.41, 95% CI = 0.91-2.20)., Conclusion: In the largest pediatric intestinal failure cohort evaluated to date, the use of ELT, compared with heparin locks, increased the risk of mechanical catheter complications. Mechanical complications carry morbidity requiring urgent clinic or emergency department visits and additional procedures. The investigation of alternative lock solutions is warranted., (© 2023 American Society for Parenteral and Enteral Nutrition.)

Background: Short bowel syndrome (SBS) is a leading cause of intestinal failure resulting in parenteral nutrition (PN) dependence and nutritional deficiencies. Long-term PN use is associated with the development of sepsis and intestinal failure-associated liver disease. Achieving enteral autonomy is the optimal way to prevent these complications. In SBS, the decreased intestinal length, bile acid deficiency, and rapid transit time contribute to fat malabsorption and continued PN dependence. We propose the use of an immobilized lipase cartridge (ILC; RELiZORB) that connects in-line with enteral feed tubing sets and is designed to breakdown the majority of fats provided in enteral nutrition (EN). Preclinical studies have demonstrated both improved fat and fat-soluble vitamin absorption with ILC use in a porcine model of SBS. To evaluate the clinical applicability of these findings, we designed a phase 3, open labeled, single center, clinical trial to determine the safety, tolerability, and efficacy of the RELiZORB enzyme cartridge when used daily with EN for 90 days., Methods: The patient population will include PN dependent children with SBS, aged 2-18 years. The primary outcome is the change in PN calories from baseline, assessed weekly throughout the study. Changes in growth Z-scores, 72-hour fecal fat and coefficient of fat absorption, plasma fatty acids and fat-soluble vitamins will also be evaluated. Assessment of change in continuous outcomes will be made using the area under the curve, expressed as a percent change relative to baseline, calculated over study day 7 to 90 (AUC7-90). The incidence of adverse events will be monitored and summarized by system organ class., Discussion: If successful, RELiZORB may offer a safe alternative to reducing PN dependence and achieving enteral autonomy in pediatric intestinal failure. These results would be clinically significant given the clear association between long-term PN use and complications in SBS., Trial Registration: ClinicalTrials.gov NCT03530852; registered on May 21st, 2018, last update posted on September 14th, 2022., Competing Interests: Dr. First and Dr. Loring were employees of Alcresta Therapeutics at the time of the protocol design. Dr. Puder and Dr. Gura receive research support and advisory compensation from Alcresta Therapeutics. Ms. Rudie has received advisory compensation from Alcresta Therapeutics. Dr. Martin receives research funding from Mead Johnson Nutrition and serves on the scientific advisory boards of LactaLogics, Plakous Therapeutics, and Vitara Biomedical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. These competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Tsikis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To compare extrahepatic adverse events during fish oil lipid emulsion (FOLE) or soybean oil lipid emulsion (SOLE) treatment in children with intestinal failure-associated liver disease (IFALD)., Study Design: In this multicenter integrated analysis, bleeding, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), infections, and signs of lipid emulsion intolerance were compared between FOLE recipients (1 g/kg/d) (n = 189) and historical controls who received SOLE (≤3 g/kg/d) (n = 73)., Results: When compared with SOLE recipients, FOLE recipients had a lower gestational age (30.5 vs 33.0 weeks; P = .0350) and higher baseline direct bilirubin (DB) (5.8 vs 3.0 mg/dL; P < .0001). FOLE recipients had a decreased incidence of bleeding (P < .0001), BPD (P < .001), ROP (P < .0156), bacterial and fungal infections (P < .0001), and lipid intolerance signs (P < .02 for all). Patients with bleeding vs patients without bleeding had higher baseline DB; the ORs for baseline DB (by mg/dL) and treatment (FOLE vs SOLE) were 1.20 (95% CI: 1.10, 1.31; P ≤ .0001) and 0.22 (95% CI: 0.11, 0.46; P ≤ .0001), respectively. In preterm infants, a higher BPD (P < .0001) and ROP incidence (P = .0071) was observed in SOLE recipients vs FOLE recipients., Conclusions: Children with IFALD who received FOLE had fewer extrahepatic adverse events, including a decreased incidence of bleeding, preterm comorbidities, and lipid intolerance signs compared with children with IFALD who received SOLE. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT00910104 and NCT00738101., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Children with intestinal failure (IF) and fever are frequently bacteremic, but risk factors for development of sepsis in this population are not well delineated. Our objective was to determine what clinical factors available on arrival to the emergency department (ED), including commonly used vital sign thresholds, predicted the subsequent development of severe sepsis in children with IF and fever., Study Design: This was a retrospective cohort study of children younger than 21 years with IF presenting to a tertiary care ED between 2010 and 2016 with fever who did not have hypotensive septic shock on arrival. The primary outcome was development of severe sepsis within 24 hours of ED arrival, as defined by consensus criteria. We identified predictors of severe sepsis using both univariate and multivariate models and calculated the test characteristics of 3 different sets of vital sign criteria in determining risk of severe sepsis., Results: In 26 (9.4%) of 278 encounters, the patient developed severe sepsis within 24 hours of arrival to the ED; 3 were excluded due to hypotensive shock on arrival. Predictors of severe sepsis included history of intestinal pseudo-obstruction (odds ratio, 8.2; 95% confidence interval, 2.3-30.2) and higher initial temperature (odds ratio, 1.7; 95% confidence interval, 1.2-2.3). The 3 sets of vital sign criteria had widely varying sensitivity and specificity in identifying development of severe sepsis., Conclusions: History of intestinal pseudo-obstruction and higher fever predicted increased risk of severe sepsis among children with IF and fever presenting to an ED. No single set of vital sign criteria had both high sensitivity and specificity for this diagnosis., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine whether the use of an immobilized lipase cartridge (ILC) to hydrolyze fats in enteral nutrition (EN) reduces parenteral nutrition (PN) dependence in a porcine model of short bowel syndrome with intestinal failure (SBS-IF). Background: SBS-IF occurs after intestinal loss resulting in malabsorption and PN dependence. Limited therapeutic options are available for achieving enteral autonomy. Methods: Eleven Yorkshire piglets underwent 75% jejunoileal resection and were randomized into control (n=6) and treatment (n = 5) groups. PN was initiated postoperatively and reduced as EN advanced if predefined clinical criteria were fulfilled. Animals were studied for 14 days and changes in PN/ EN calories were assessed. Intestinal adaptation, absorption, and nutrition were evaluated at the end of the study (day 15). Comparisons between groups were performed using analysis of covariance adjusted for baseline. Results: ILC animals demonstrated a 19% greater reduction in PN calories (P < 0.0001) and higher mean EN advancement (66% vs 47% of total calories, P < 0.0001) during the 14-day experiment. Treatment animals had increased intestinal length (19.5 vs 0.7%, P=0.03) and 1.9-fold higher crypt cell proliferation (P=0.02) comparedwith controls. By day 15, ILC treatment resulted in higher plasma concentrations of glucagon-like peptide-2 (P = 0.02), eicosapentaenoic acid (P < 0.0001), docosahexaenoic acid (P = 0.004), vitamin A (P = 0.02), low-density lipoprotein (P = 0.02), and high-density lipoprotein (P = 0.04). There were no differences in liver enzymes or total bilirubin between the two groups. Conclusions: ILC use in conjunction with enteral feeding reduced PN dependence, improved nutrient absorption, and increased bowel growth in a porcine SBS-IF model. These results support a potential role for the ILC in clinical SBS-IF. [ABSTRACT FROM AUTHOR]

Background: Parenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure-associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease. Objective: We sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines. Design: Prospectively collected data for patients treated with FO at Boston Children's Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy. Results: Among 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) γ-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end-stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of ≥15, history of gastrointestinal bleeding, age at FO initiation ≥16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure. Conclusions: Most infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition-dependent patients is recommended. This trial was registered at clinicaltrials.gov as NCT00910104. [ABSTRACT FROM AUTHOR]

Long-term parenteral nutrition (PN) carries the risk of progressive liver disease in infants with intestinal failure. Although PN-associated liver disease (PNALD) is multifactorial in etiology, components of soybean oil lipid emulsions have been implicated in the disease's pathogenesis. Historically, infants with PNALD who were unable to wean from PN to full enteral feeding developed cirrhosis and end-stage liver disease, which require liver transplantation to survive. Over the past 2 decades, novel strategies for the management of parenteral lipids have improved morbidity and mortality from PNALD in infants with intestinal failure. Current strategies for the treatment of PNALD include restricting the dose of parenteral soybean oil lipid emulsion and/or replacing the soybean oil with a parenteral fish-oil lipid emulsion or emulsions of mixed-lipid sources. The purpose of this report is to review published data that evaluate these strategies in parenteral lipid management for the treatment and prevention of PNALD. [ABSTRACT FROM AUTHOR]

Abstract: The neonatal intestine is a complex organ that regulates the absorption of nutrients essential for growth and development. Intestinal failure results from insufficient or functionally inadequate bowel and can lead to failure of neonatal growth and development. Current literature on neonatal intestinal physiology and failure was reviewed and summarized. A homeostatic interplay of electrolytes, enzymes, and hormonal regulators is essential to achieve the physiologic balance needed for adequate intestinal performance. Physiologic consequences of intestinal failure are dependent on the length and anatomic location of the diseased or surgically resected bowel. Intestinal failure leads to disruption of normal intestinal physiology and may have long-term consequences for growth and development if inadequately treated. Parenteral nutrition remains the mainstay of treatment for neonatal intestinal failure. [Copyright &y& Elsevier]

Abstract: Purpose: This study compares postoperative markers of liver injury in patients receiving intravenous fish oil (IFO) with parenteral nutrition (PN)–associated cholestasis (PNAC) to patients with resolved PNAC. Methods: A retrospective review of all cholestatic-IFO patients undergoing abdominal laparotomy between March 1, 2007, and July 1, 2009, led to inclusion of 23 patients who collectively underwent 27 abdominal operations (13 pre-PNAC resolution and 14 post-PNAC resolution). Direct bilirubin (DB), total bilirubin, and alanine aminotransferase levels were examined over time in relation to operations. The time to resume presurgical trend of decreasing DB was calculated. Results: Sixty-nine percent (9/13) of pre-PNAC resolution procedures were associated with postoperative increase in DB compared with 7% (1/14) of post-PNAC resolution procedures associated with a recurrence of cholestasis (P = .02; odds ratio, 29.3; 95% confidence interval, 2.79-306.8). The median time to return to the preoperative downward trend of DB was 21 days. Conclusions: Operations before PNAC resolution may be associated with an increased postoperative DB, possibly reflecting an exacerbation of liver injury. Operations post-PNAC resolution on IFO had a comparatively low incidence of postoperative cholestasis recurrence. Excepting clinical indication otherwise, it may be advisable to delay surgical intervention in the setting of PNAC in certain cases. [ABSTRACT FROM AUTHOR]

Children with intestinal failure (IF) suffer from insufficient intestinal length or function, making them dependent on parenteral nutrition (PN) for growth and survival. PN and its components are associated with many complications ranging from simple electrolyte abnormalities to life-threatening PN-associated liver disease, which is also called intestinal failure-associated liver disease (IFALD). From a nutrition perspective, the ultimate goal is to provide adequate caloric requirements and make the transition from PN to full enteral nutrition (EN) successful. Upon review of the literature, we have summarized the most effective and innovative PN and EN therapies for this patient population. Antibiotic-coated catheters and antibiotic or ethanol locks can be implemented, as they appear effective in reducing catheter-related infection and thus further reduce the risk of IFALD. Lipid emulsions should be given judiciously. The use of an omega-3 fatty acid-based formulation should be considered in patients who develop IFALD. Trophic feeding is important for intestinal adaptation, and EN should be initiated early to help wean patients from PN. Long-term management of children with IF continues to be an emerging field. We have entered uncharted territory as more children survive complications of IF and IFALD. Careful monitoring and individualized management to ensure maintenance of growth while avoiding complications are the keys to successful patient outcomes. [Copyright &y& Elsevier]