Differential Effects on Intestinal Adaptation Following Exogenous Glucagon‐Like Peptide 2 Therapy With and Without Enteral Nutrition in Neonatal Short Bowel Syndrome

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.     

Glucagon‐Like Peptide 2 Stimulates Postresection Intestinal Adaptation in Preterm Pigs by Affecting Proteins Related to Protein,Carbohydrate, and Sulphur Metabolism

Background: Exogenous glucagon‐like peptide 2 (GLP‐2) stimulates intestinal adaptation after resection in animal models of pediatric short bowel syndrome (SBS). It is unknown whether the molecular mechanisms of such GLP‐2 effects are similar to those of postresection spontaneous adaptation. Using preterm pigs as a model, we hypothesized that GLP‐2 treatment would change the intestinal proteome within the first week after resection, relative to individuals not resected or resected without GLP‐2 treatment. Materials and Methods: Two‐day‐old preterm pigs were subjected to resection of 50% distal small intestine and fed total parenteral nutrition without (SBS) or with GLP‐2 infusion (3.5 µg/kg/h, SBS+GLP‐2) for 5 days. The proteome of the remnant proximal intestine was compared among the SBS, SBS+GLP‐2, and unresected pigs, through gel‐based proteomics. Results: Thirty‐two proteins with differential expression were identified. Ten of these proteins were affected by the resection alone (ie, SBS vs unresected pigs). Five of these resection‐responsive proteins and another 22 proteins were affected by GLP‐2 infusion (ie, SBS+GLP‐2 vs SBS or unresected pigs). Resection alone mainly affected cellular structural proteins, while the added GLP‐2 treatment affected proteins involved in protein processing and the metabolism of protein, carbohydrate, and sulphur. Conclusion: In the first days following resection, proteins affected by resection plus GLP‐2 treatment differed markedly from those affected by the spontaneous intestinal adaptation following resection alone. Whether more long‐term GLP‐2 treatment may affect the intestinal proteome following intestinal resection remains unknown.     

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.     

Modulation of Intestinal Inflammation by Minimal Enteral Nutrition With Amniotic Fluid in Preterm Pigs

Background: Necrotizing enterocolitis (NEC) is a severe inflammatory disorder, associated with the difficult transition from parenteral to enteral feeding after preterm birth. We hypothesized that minimal enteral nutrition (MEN) with amniotic fluid (AF), prior to enteral formula feeding, would improve resistance to NEC in preterm pigs. Methods: Experiment 1: IEC‐6 cells were incubated with porcine (pAF) and human AF (hAF) to test AF‐stimulated enterocyte proliferation and migration in vitro. Experiment 2: Cesarean‐delivered, preterm pigs were fed parenteral nutrition and MEN with pAF, hAF, or control fluid (MEN‐pAF, MEN‐hAF, or MEN‐CTRL; all n = 9) for 2 days before tissue collection. Experiment 3: Preterm pigs were fed MEN diets as in experiment 2, but followed by 2 days of enteral formula feeding, which predisposes to NEC (NEC‐pAF, NEC‐hAF, or NEC‐CTRL; n = 10–12). Results: Both pAF and hAF stimulated enterocyte proliferation and migration in vitro. In experiment 2, MEN‐pAF and MEN‐hAF pigs showed increased body weight gain and reduced intestinal interleukin (IL)–8 and colonic IL‐6 levels, indicating reduced inflammatory response. In experiment 3, body weight gain was highest in the 2 groups fed AF as MEN, but NEC incidences were similar (NEC‐pAF) or increased (NEC‐hAF) compared with controls. Conclusions: Intake of pAF or hAF improved body growth and modulated intestinal inflammatory cytokines during a period of parenteral nutrition, but did not protect against later formula‐induced NEC in preterm pigs. Further studies are required to show if MEN feeding with species‐specific AF, combined with an optimal enteral diet (eg, human milk), will improve adaptation during the transition from parenteral to enteral feeding in preterm neonates.     

Acute Effects of a Glucagon‐Like Peptide 2 Analogue,Teduglutide, on Gastrointestinal Motor Function and Permeability in Adult Patients With Short Bowel Syndrome on Home Parenteral Nutrition

Background: Glucagon‐like peptide 2 (GLP‐2) agonists decrease the need for parenteral nutrition (PN) in short bowel syndrome (SBS); mechanisms evaluated to date have focused on the intestinotrophic effect of GLP‐2 agonists such as increased absorptive capacity of the remnant intestine and increased citrulline levels. Other mechanisms may also play a role in effects of GLP‐2 agonists. Aim: To measure effects of a GLP‐2 agonist, teduglutide (TED), compared with placebo (PLA) on gastric emptying (GE), overall gut transit, fluid balance, intestinal monosaccharide absorption, and permeability in patients with SBS on home PN (HPN). Materials and Methods: In 8 adults with SBS on HPN, we compared daily subcutaneous TED (0.05 mg/kg) and PLA (crossover design, each treatment 7 days with a 14‐day washout) on gut transit, intestinal absorption, and permeability after oral mannitol (200 mg) and lactulose (1 g), as well as stool weight and urine volume over 8 hours. Analysis used the paired t test. Results: Of 8 patients, 4 were men, with a mean ± SD age of 54 ± 1 years, body mass index of 25 ± 4 kg/m², residual small intestine of 63 ± 12 cm, and 25% ± 15% of residual colon. The overall gut transit (% emptied at 6 hours) was 53.4% ± 15% for TED vs 62.4% ± 15.2% for PLA (P = .075), with no effect on GE (P = .74). TED increased urine mannitol excretion at 0–2 hours (16.2 ± 3.6 mg TED vs 11.3 ± 2.2 mg PLA, P = .20) and 0–8 hours (32.7 ± 5.9 mg PLA vs 48.8 ± 8.9 mg TED, P = .17). There were no differences in urine lactulose excretion or lactulose/mannitol ratio (0.024 ± 0.005 TED vs 0.021 ± 0.005 PLA). Over 8 hours, TED (vs PLA) numerically reduced stool weight (mean ± SEM, 77 ± 18 g TED vs 106 ± 43 g PLA, P = .42) and increased urine volume (408.9 ± 52.2 mL TED vs 365.7 ± 57.3 mL PLA, P = .34). Conclusion: Seven‐day TED treatment in 8 participants suggests beneficial effects on fluid balance and monosaccharide absorption, and it retarded overall gut transit with no effects on GE or mucosal permeability. Larger, longer, mechanistic studies of TED in SBS are warranted. This trial was registered at clinicaltrials.gov as NCT02099084.     

Prospective Cohort Study of the Outcome of and Risk Factors for Intravascular Catheter‐Related Bloodstream Infections in Children With Intestinal Failure

Background: Children with intestinal failure (IF) have frequent catheter‐related bloodstream infections (CRBSIs). The purpose of this study was to prospectively study the clinical course of CRBSIs and to seek modifiable risk factors for CRBSIs in children with IF. Materials and Methods: Children with IF were enrolled prospectively and data on potential risk factors collected monthly. Additional data were collected when they had CRBSIs. Results: Sixteen children were enrolled, yielding 223 months of data. The rate of CRBSIs was 4.6 per 1000 catheter days. The most consistent symptom at onset of CRBSI was fever (28 of 32 cases). Elevated C‐reactive protein (CRP) was the only laboratory abnormality that was consistently associated with the onset of CRBSI (elevated in 15 of the 18 cases where it was measured). Combining all episodes in the cases that relapsed, the catheter salvage rate was 17 of 29 (59%), including 4 of 11 polymicrobial CRBSIs. Risk factors for CRBSI included double lumen tunneled central venous catheter (CVC), jugular placement of CVC, higher doses of intralipid, and having <50 cm small bowel postresection. Conclusion: The diagnosis of CRBSI should be questioned in the absence of fever and/or elevated CRP. Salvage of catheters should be attempted with all bacterial CRBSIs, assuming that the child is stable since the CVC can be retained in the majority of cases.     

Ethanol Lock Efficacy and Associated Complications in Children With Intestinal Failure

Background: Prophylactic ethanol lock therapy (ELT) reduces central line–associated bloodstream infections (CLA‐BSIs) in children with intestinal failure (IF). However, the risk of associated complications is unclear. We aim to describe our experience with prophylactic ethanol locks in a cohort of patients with IF. Materials and Methods: Thirty patients on ELT from 2010–2013 were identified by review of our intestinal rehabilitation registry. Patient demographics, CLA‐BSI events, and line complications were extracted. Comparisons in infection and complication rates when on and off ELT were made using a Poisson mixed‐effect regression model. Results: CLA‐BSIs when on and off ELT were 3.1 and 5.5 per 1000 catheter days, respectively (P < .015). Overall complication rates were similar in both groups. In those patients who experienced a complication, the complication rates on ELT compared with time off ELT were significantly lower (P < .003). Line perforation or breakage rates declined significantly when on ELT, from 1.8 to 1.53 per 1000 catheter days (P < .006). Line occlusion rates also decreased on ELT, from 0.6 to 0.3 per 1000 catheter days (P = .056). Infecting organisms were not different on and off ELT, and patients experienced a similar number of polymicrobial infections on or off therapy. Klebsiella pneumoniae was the most common infecting organism in both groups. Conclusions: Ethanol lock therapy use reduces both CLA‐BSI and central line complication rates in children with IF. These results underscore the safety and efficacy of ELT use in this population.     

Longitudinal Bone Mineralization Assessment in Children Treated With Long‐Term Parenteral Nutrition for Severe Intestinal Failure

Background: Metabolic bone disease is common in children receiving home parenteral nutrition (HPN) for intestinal failure (IF). Long‐term evolution of bone mass in pediatric IF is poorly documented. The aims of this study were (1) to determine the prevalence of low bone mass (LBM) in children receiving HPN for IF, (2) to evaluate the evolution of total bone mineral content (TBMC) during HPN with dual‐energy x‐ray absorptiometry (DXA), and (3) to identify related factors. Methods: All children referred in our HPN center from 2004 to 2014 were eligible. Inclusion criteria were HPN dependence due to noninflammatory IF, at least 2 TBMC assessments, and HPN duration of at least 2 years at last DXA. TBMC was expressed in z score for ideal weight for height (WFH). LBM was defined by a TBMC WFH z score ≤–2 standard deviations (SD). Results: A total of 175 DXAs for 31 children were performed, mean of 5.6 ± 2.9 assessments per child. The median time between first and last DXA recorded was 6.2 years (0.7–16.6). At the first DXA, 14 children (45%) had a LBM. TBMC increased by +0.1 ± 0.04 SD per year of HPN (P = .012). The risk of LBM decreased with an odds ratio of 0.9 per year of HPN (95% confidence interval, 0.92–0.99; P = .018). Lean mass z score and calcium parenteral intakes were related to the TBMC improvement. Conclusion: LBM is common in pediatric IF, but bone status could improve during HPN in these children.     

Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric‐Onset Intestinal Failure

Background: Intestinal failure (IF)–associated liver disease (IFALD) is the major cause of mortality in IF. The link between intestinal microbiota and IFALD is unclear. Methods: We compared intestinal microbiota of patients with IF (n = 23) with healthy controls (n = 58) using culture‐independent phylogenetic microarray analysis. The microbiota was related to histological liver injury, fecal markers of intestinal inflammation, matrix metalloproteinase 9 and calprotectin, and disease characteristics. Results: Overabundance of Lactobacilli, Proteobacteria, and Actinobacteria was observed in IF, whereas bacteria related to Clostridium clusters III, IV, and XIVa along with overall diversity and richness were reduced. Patients were segregated into 3 subgroups based on dominating bacteria: Clostridium cluster XIVa, Proteobacteria, and bacteria related to Lactobacillus plantarum. In addition to liver steatosis and fibrosis, Proteobacteria were associated with prolonged current parenteral nutrition (PN) as well as liver and intestinal inflammation. Lactobacilli were related to advanced steatosis and fibrosis mostly after weaning off PN without associated inflammation. In multivariate permutational analysis of variance, liver steatosis, bowel length, PN calories, and antibiotic treatment best explained the microbiota variation among patients with IF. Conclusions: Intestinal microbiota composition was associated with liver steatosis in IF and better predicted steatosis than duration of PN or length of the remaining intestine. Our results may be explained by a model in which steatosis is initiated during PN in response to proinflammatory lipopolysaccharides produced by Proteobacteria and progresses after weaning off PN, as the L plantarum group Lactobacilli becomes dominant and affects lipid metabolism by altering bile acid signaling.     

Parenteral ω‐3 Fatty Acid Lipid Emulsions for Children With Intestinal Failure and Other Conditions

Background: There is growing interest in the use of ω‐3 fatty acid (n‐3FA) lipid emulsions to prevent complications associated with parenteral nutrition. The authors systematically reviewed the evidence on the benefits and safety of n‐3FA compared with standard lipid emulsions in children with intestinal disease, critical illness, trauma, or postoperative complications. Materials and Methods: The authors searched 4 bibliographic databases from their inception to March 2011, conference proceedings, trial registries, and reference lists. Two reviewers independently selected studies, assessed methodological quality, and rated the strength of the evidence. One reviewer extracted and a second reviewer verified data. The authors summarized findings qualitatively and conducted meta‐analysis when appropriate. Results: Five randomized controlled trials with unclear risk of bias and 3 high‐quality prospective cohort studies were included. The studies examined premature, low birth weight infants (n = 6) and children with heart disease (n = 1) or intestinal failure (n = 1). The strength of evidence was consistently low or very low across all lipid emulsion comparisons and outcomes. In young children, n‐3FA emulsions resulted in improvement in some biochemical outcomes of intestinal failure–associated liver disease but no difference in mortality. Few studies examined patient‐important outcomes, such as length of hospital and intensive care stay; need for transplantation, growth, and cognitive development; or the long‐term effects and potential harms associated with these therapies. Conclusions: Currently, there is a lack of sufficient high‐quality data to support the use of parenteral n‐3FA lipid emulsions in children. Future trials examining long‐term clinical outcomes and harms are needed.     

The Type of Fat in the Diet Influences Regulatory Aminopeptidases of the Renin-Angiotensin System and Stress in the Hypothalamic-Pituitary-Adrenal Axis in Adult Wistar Rats

(1) Background: Prolonged feeding with a high-fat diet (HFD) acts as a stressor by activating the functions of the hypothalamic-pituitary-adrenal gland (HPA) stress axis, accompanied of hypertension by inducing the renin-angiotensin-aldosterone system. Angiotensinases enzymes are regulatory aminopeptidases of angiotensin metabolism, which together with the dipeptidyl peptidase IV (DPP-IV), pyroglutamyl- and tyrosyl-aminopeptidase (pGluAP, TyrAP), participate in cognitive, stress, metabolic and cardiovascular functions. These functions appear to be modulated by the type of fat used in the diet. (2) Methods: To analyze a possible coordinated response of aminopeptidases, their activities were simultaneously determined in the hypothalamus, adenohypophysis and adrenal gland of adult male rats fed diets enriched with monounsaturated (standard diet (S diet) supplemented with 20% virgin olive oil; VOO diet) or saturated fatty acids (diet S supplemented with 20% butter and 0.1% cholesterol; Bch diet). Aminopeptidase activities were measured by fluorimetry using 2-Naphthylamine as substrates. (3) Results: the hypothalamus did not show differences in any of the experimental diets. In the pituitary, the Bch diet stimulated the renin-angiotensin system (RAS) by increasing certain angiotensinase activities (alanyl-, arginyl- and cystinyl-aminopeptidase) with respect to the S and VOO diets. DPP-IV activity was increased with the Bch diet, and TyrAP activity decrease with the VOO diet, having both a crucial role on stress and eating behavior. In the adrenal gland, both HFDs showed an increase in angiotensinase aspartyl-aminopeptidase. The interrelation of angiotensinases activities in the tissues were depending on the type of diet. In addition, correlations were shown between angiotensinases and aminopeptidases that regulate stress and eating behavior. (4) Conclusions: Taken together, these results support that the source of fat in the diet affects several peptidases activities in the HPA axis, which could be related to alterations in RAS, stress and feeding behavior.     

Enteral L‐Arginine Supplementation for Prevention of Necrotizing Enterocolitis in Very Low Birth Weight Neonates

Background: Necrotizing enterocolitis (NEC) is the most common acquired gastrointestinal disease in premature infants and has high mortality and morbidity. Endothelial nitric oxide is an important regulator of vascular perfusion and is synthetized from the amino acid L‐arginine. Hypoargininemia is frequently observed in preterm neonates and may predispose them to NEC. Our objective was to determine the effect of enteral L‐arginine supplementation on the incidence and severity of NEC in very low birth weight (VLBW) neonates. Materials and Methods: We conducted a parallel blind randomized pilot study, comprising VLBW neonates with birth weight ≤1500 g and gestational age ≤34 weeks. VLBW neonates were randomly assigned to receive enteral L‐arginine supplementation (1.5 mmol/kg/d bid) between the 3rd and 28th day of life or placebo. Diagnosis and classification of NEC were done according to modified Bell's criteria. Results: Eighty‐three neonates were randomized to the arginine (n = 40) or placebo (n = 43) group. No adverse effects were observed in neonates receiving L‐arginine supplementation. The incidence of NEC stage III was significantly lower in the arginine‐supplemented group (2.5% vs 18.6%, P = .030). Conclusions: Enteral L‐arginine supplementation of 1.5 mmol/kg/d bid can be safely administered in VLBW neonates from the 3rd to the 28th day of life. Enteral L‐arginine supplementation appears to reduce the incidence of stage III NEC in VLBW infants. Larger studies are needed to further evaluate the effect of L‐arginine supplementation in preventing NEC in VLBW infants.     

Effects of Ethanol Lock Therapy on Central Line Infections and Mechanical Problems in Children With Intestinal Failure

Objectives: Although use of 70% ethanol lock therapy (ELT) has been shown to decrease the rate of catheter‐related bloodstream infections (CRBSIs) in patients with intestinal failure and central venous catheters (CVCs), concerns have been raised about its association with higher rates of mechanical problems and CVC replacements (CVC‐Rs). We sought to compare the rates of CRBSI, mechanical problems, and CVC‐Rs in a cohort of pediatric patients with intestinal failure, with and without ELT (ELT⁺ and ELT^?, respectively). Methods: Data were collected in a retrospective chart review from February 2007 to May 2014. Mann‐Whitney and Wilcoxon signed‐rank tests were used to compare nonparametric and paired data, respectively. Results: Twenty‐nine children had 9033 catheter days (CDs). The ELT⁺ group (vs ELT^?) had lower rate of infection and significantly fewer CVC‐Rs due to infection but significantly more mechanical events and related CVC‐Rs with significantly shorter mean CVC survival. In 13 children who had a pre‐ELT and post‐ELT period, ELT was associated with a decrease in the rate of CVC‐Rs due to infection (0.36 vs 4.74/1000 CDs, P = .046) and an increase in the rate of CVC‐Rs due to mechanical problems (5.05 vs 0/1000 CDs, P = .018). Conclusions: While ELT⁺ is associated with a lower rate of CRBSIs and related CVC‐Rs, it is also associated with higher rates of mechanical problems and related CVC‐Rs. In addition to investigating the ideal concentration, duration, and timing of ELT to preserve the integrity of the CVC, alternatives to exclusively ethanol‐based lock solutions should be developed.     

Systematic Review and Meta‐Analysis of the Utilization of Ethanol Locks in Pediatric Patients With Intestinal Failure

Background : Intestinal failure is a chronic condition related to loss of bowel length and/or function, resulting in dependence on central venous catheters for fluids and nutrition. Catheter use can be associated with significant complications, including catheter‐related bloodstream infections (CRBSIs), which can lead to loss of vascular access, advancing intestinal failure associated–liver disease and death. Our objective was to evaluate the effectiveness and safety of ethanol locks as compared with standard heparin locks in pediatric intestinal failure. Methods : Databases, including MEDLINE and EMBASE, were searched until March 2017. Titles and abstracts were reviewed independently and relevant articles reassessed by full‐text review. The main outcome was the rate of CRBSIs, while secondary outcomes were catheter replacement and repair. Results : Nine observational studies were included. The mean difference in rate of CRBSIs was 6.27 per 1000 catheter days (95% CI, 4.89–7.66) favoring ethanol locks, with a 63% overall reduction in infection rate. The mean difference in catheter replacement rate (per 1000 catheter days) was 4.56 (95% Cl, 2.68–6.43) favoring ethanol locks. The overall effect on catheter repair rate (per 1000 catheter days) was ?1.67 (95% CI, ?2.30 to ?1.05), indicating lower repair rate with heparin locks. Conclusion : Sufficient evidence was noted showing that ethanol locks reduced CRBSIs and catheter replacements. Our findings raise questions about the effect of the ethanol lock on catheter integrity based on the noted increase in repair rate. This requires further prospective evaluation and may support selective application of ethanol locks to patients with documented CRBSIs.     

Increased Anti‐Flagellin and Anti‐Lipopolysaccharide Immunoglobulins in Pediatric Intestinal Failure

Background: Central line–associated bloodstream infections (CLABSIs) pose a significant challenge in the lives of patients with intestinal failure (IF). We hypothesized that plasma immunoglobulins against flagellin (FLiC) and lipopolysaccharide (LPS) would be able to differentiate CLABSIs from nonbacterial febrile episodes and that levels would increase with infection and decline following appropriate antibiotic treatment. Materials and Methods: Patients with IF, due to short bowel syndrome, between the ages of 3 months and 4 years of age, were recruited at Cincinnati Children's Hospital Medical Center. Anti‐FLiC and anti‐LPS plasma antibody levels were measured in 13 children with IF at baseline, during febrile events, and also following treatment with antibiotics. These were also measured in 11 healthy children without IF who were recruited as controls. Results: Plasma anti‐FLiC IgA levels increased during febrile episodes in all patients with IF (baseline mean of 1.10 vs febrile episode mean of 1.32 optical density units, respectively; P = .046). Neither plasma anti‐FLiC nor anti‐LPS IgA or IgG levels distinguished CLABSI from nonbacterial febrile episodes compared with baseline levels. Compared with controls, patients with IF had significantly higher plasma levels of anti‐FLiC and anti‐LPS IgA at baseline. Conclusion: Plasma anti‐FLiC IgA antibody levels rise during febrile episodes but do not differentiate between nonbacterial febrile illnesses and CLABSIs in pediatric IF. However, the upregulation of these antibodies in IF suggests the baseline systemic presence of Gram‐negative bacterial products.     

Long‐Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure–Associated Liver Disease

Background: Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF‐associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long‐term PN and FOLE therapy due to chronic IF. Materials and Methods: A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease. Results: Of 215 patients with IFALD treated from 2004–2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight‐for age and length‐for‐age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term. Conclusions: Children with IFALD who required long‐term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation.     

Factors Affecting Spontaneous Closure of Gastrocutaneous Fistulae After Removal of Gastrostomy Tubes in Children With Intestinal Failure

Background: Children with intestinal failure (IF) frequently require gastrostomy tubes (GTs) for long‐term nutrition support. Risk factors for persistent gastrocutaneous fistulae (GCFs) in pediatric patients with IF are largely unknown but may include underlying nutrition status and duration of indwelling GT. Materials and Methods: Records of patients with IF having undergone GT removal and allowed a trial at spontaneous closure were reviewed. Nonparametric continuous variables were analyzed using the Wilcoxon rank sum test. Post hoc analysis was performed to identify the optimal threshold of GT duration predicting probability of spontaneous closure identified using receiver operating characteristic curve analysis. Results: Fifty‐nine children with IF undergoing GT removal were identified. Spontaneous closure occurred in 36 (61%) sites, while 23 (39%) underwent operative closure at a median 67 days after GT removal. The duration of indwelling GT was significantly shorter in the spontaneous closure group (11.5 vs 21 months, P = .002). Of 33 GT indwelling for ≤18 months, 28 (85%) closed spontaneously, compared with only 9 of 26 (35%) with duration >18 months (P < .001). With GCF persisting beyond 7 days, only 21% (6/28) of sites closed spontaneously, but this dropped to 6% (1/18) of cases with concurrent GT duration >18 months. Conclusions: Of the risk factors evaluated, only prolonged GT duration was associated with an increased likelihood of failure to close spontaneously. It is significantly less likely in pediatric patients with IF in whom GCF persists >7 days, particularly if the duration of GT is >18 months. Relatively earlier operative closure should be considered in this group.