Red cell abnormalities characterized by ektacytometry in children with cholestasis.

BACKGROUND: Spur-cell anemia sometimes accompanies cholestasis. We postulated that even in the absence of spur-cells, cholestasis might alter red blood cell (RBC) osmotic fragility and deformability. Therefore, we assessed these RBC measures by ektacytometry in pediatric patients. METHODS: We conducted a single center, prospective, cross-sectional investigation of RBC membrane characteristics by ektacytometry in pediatric patients with intra- and extrahepatic cholestasis followed at Cincinnati Children's Hospital Medical Center. We measured red cell membrane fragility and deformability in 17 patients with cholestasis and 17 age-matched controls without cholestasis. RESULTS: Patients with cholestasis had decreased RBC osmotic fragility compared to controls, with a significant left shift in Omin, indicating increased RBC surface-to-volume ratio. One showed spur cell morphology. However, the other 16 had no spurring, indicating that ektacytometry is a sensitive method to detect RBC membrane abnormalities. Left shift of Omin positively correlated with serum conjugated bilirubin levels and even more negatively with serum vitamin E concentration. CONCLUSIONS: This study suggests that subclinical red blood cell membrane abnormalities exist in most pediatric patients with cholestasis, increasing risk for hemolysis when subjected to oxidative stress. Hence minimizing pro-oxidants exposure and maximizing antioxidant exposure is advisable for this group. GOV IDENTIFIER: NCT05582447 https://clinicaltrials.gov/ct2/show/NCT05582447?cond=Cholestasis&cntry=US&state=US%3AOH&city=Cincinnati&draw=2&rank=2 . IMPACT: Spur cell anemia due to decreased red cell osmotic fragility and decreased deformability has been reported among patients with cholestasis. Ektacytometry is a reliable, reproducible method to measure red cell osmotic fragility and deformability. Few data describe red cell osmotic fragility or deformability in patients with cholestasis who may or may not have spur cell anemia. Ektacytometry shows that red cell osmotic fragility and deformability are decreased in many children with cholestasis even when spur cell anemia has not yet occurred. Factors associated with decreased osmotic fragility include elevated serum bilirubin, elevated serum bile acids, and decreased serum vitamin E.

Chronic Mucosal Inflammation in Pediatric Intestinal Failure Patients-A Unique Phenomenon.

INTRODUCTION/OBJECTIVES: As intestinal failure (IF) management improves and long-term survival rate increases, its physiological complications have become more apparent. The development of chronic intestinal inflammation resembling inflammatory bowel disease (IBD) in this population has been reported, but the literature describing it in detail is sparse. The present study was designed to characterize children with IF who developed chronic intestinal inflammation and identify the potential predisposing clinical factors. METHODS: This retrospective study was based on the electronic medical records of pediatric patients seen at the Cincinnati Children's Hospital Medical Center between January 2000 and July 2022. Demographic and medical history data were collected and compared between children with IF that developed chronic intestinal inflammation and children with IF that did not develop chronic intestinal inflammation. RESULTS: During the follow-up period, 23 children were diagnosed with chronic intestinal inflammation. Of these, 12 (52%) were males, with a median age of 4.5 (3-7) years at diagnosis. Nearly one-third of the patients had gastroschisis (31%), followed by necrotizing enterocolitis (26%), and malrotation and volvulus (21.7%). More children in the chronic intestinal inflammation group lacked an ileocecal valve (ICV) and adjoining distal ileum as compared to the short bowel syndrome (SBS)-IF control group (15 patients, 65% vs 8 patients, 33%). Moreover, more children in the chronic intestinal inflammation group had undergone a prior lengthening procedure than the SBS-IF control group (5 patients, 21.7% vs. 0, respectively). DISCUSSION: SBS patients are at risk of relatively early onset chronic intestinal inflammation. The absence of an ICV (and adjoin ileum) and prior lengthening procedures emerge as factors associated with the risk of IBD in these patients.

Pitfalls of iron supplementation in parenteral nutrition admixtures for children with intestinal failure.

BACKGROUND: Pediatric patients with intestinal failure are at increased risk for iron deficiency. Supplementation is not routinely included in parenteral nutrition solutions. There is currently limited research related to the safety of iron supplementation in parenteral nutrition and for intravenous forms used in patients with intestinal failure. Current American Society for Parenteral and Enteral Nutrition and ESPGHAN guidelines promote the use of enteral iron, acknowledging the risks of using iron supplementation within parenteral nutrition admixtures. METHODS: We review a patient case and the current available literature related to iron in parenteral nutrition. RESULTS: Five major concerns are identified: peroxidation reactions, incompatibility, hypersensitivity, infection risk, and iron overload. CONCLUSION: We propose an argument against the preferential use of iron supplementation within parenteral nutrition in children with intestinal failure when enteral supplementation or intermittent parenteral infusion may be sufficient.

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.

Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study.

BACKGROUND: This study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF). METHODS: A 24-week, phase III trial with 2 randomized, double-blind teduglutide dose groups and a nonblinded standard of care (SOC) arm was used; patients received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily. Safety end points included treatment-emergent adverse events (TEAEs) and growth parameters. The primary efficacy/pharmacodynamic end point was the number of patients who achieved a ≥20% reduction in parenteral support (PS) from baseline at week 24. RESULTS: All 59 enrolled patients completed the study (0.025 mg/kg, n = 24; 0.05 mg/kg, n = 26; SOC, n = 9). Baseline demographics and disease characteristics were comparable among groups. TEAEs were reported by 98% and 100% of patients in the teduglutide and SOC groups, respectively. The most common TEAEs in the teduglutide-treated groups were pyrexia and vomiting. The primary end point was achieved by 13 (54.2%), 18 (69.2%), and 1 (11.1%) patients who received 0.025 mg/kg teduglutide, 0.05 mg/kg teduglutide, and SOC, respectively (P < 0.05 vs SOC). Both 0.025-mg/kg and 0.05-mg/kg teduglutide groups showed clinically significant reductions in PS volume (P < 0.05 vs SOC), PS calories, days per week and hours per day of PS infusions, and increases in enteral nutrition and plasma citrulline at week 24 compared with baseline. Two (8.3%, 0.025 mg/kg teduglutide) and 3 patients (11.5%, 0.05 mg/kg teduglutide) achieved enteral autonomy. CONCLUSION: The safety profile of teduglutide was similar to that reported previously in children and adults. Treatment with teduglutide was associated with significant reductions in PS for pediatric patients with SBS-IF over 24 weeks.

Evidence-Based Strategies and Recommendations for Preservation of Central Venous Access in Children.

Children with chronic illness often require prolonged or repeated venous access. They remain at high risk for venous catheter-related complications (high-risk patients), which largely derive from elective decisions during catheter insertion and continuing care. These complications result in progressive loss of the venous capital (patent and compliant venous pathways) necessary for delivery of life-preserving therapies. A nonstandardized, episodic, isolated approach to venous care in these high-need, high-cost patients is too often the norm, imposing a disproportionate burden on affected persons and escalating costs. This state-of-the-art review identifies known failure points in the current systems of venous care, details the elements of an individualized plan of care, and emphasizes a patient-centered, multidisciplinary, collaborative, and evidence-based approach to care in these vulnerable populations. These guidelines are intended to enable every practitioner in every practice to deliver better care and better outcomes to these patients through awareness of critical issues, anticipatory attention to meaningful components of care, and appropriate consultation or referral when necessary.

Esophageal dysmotility: An intrinsic feature of megacystis, microcolon, hypoperistalsis syndrome (MMIHS).

OBJECTIVES: Megacystis-microcolon-hypoperistalsis syndrome (MMIHS) also called Berdon's Syndrome, is a smooth muscle myopathy that results in an enlarged bladder, microcolon, and small bowel hypoperistalsis. In our series of six patients with this disorder, all had disordered swallowing. Therefore, we prospectively characterized esophageal structure and function in all. METHODS: Diagnoses had been established by contrast radiography, small bowel manometry, and urodynamic studies. To investigate the esophagus, we endoscoped and biopsied the esophagus of each patient on multiple occasions. All patients also underwent water soluble contrast esophagography and esophageal manometry. RESULTS: Upon careful questioning, all patients had swallowing dysfunction, and the majority of their enteral intake was via gastrostomy or gastrojejunostomy. All took some oral alimentation, but eating was slow and none could aliment themselves completely by the oral route, receiving 50% or less of their calories by mouth. Four had megaesophagus whereas the esophagus of the two youngest was of normal caliber. All had eosinophilic esophagitis and/or esophageal Candidiasis from time to time, but successful treatment of these findings failed to improve their symptoms. Manometry revealed normal lower esophageal sphincter (LES) resting tone and normal LES relaxation, but for all, peristalsis was absent in the esophageal body. CONCLUSIONS: This series expands the spectrum of findings in MMIHS, to include a primary motility disorder of the esophageal body. As patients age, the esophageal caliber appears to increase. Successful treatment of neither esophageal eosinophilia nor Candidiasis is effective in ameliorating the motility disorder. If our findings are confirmed in more patients with MMIHS, this disorder should be renamed, megacystis-microcolon-intestinal-and esophageal hypoperistalsis syndrome. TYPE OF STUDY: Prognosis study, Level IV (case series).

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.

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.

Limited surgical resection for graft salvage following recovery from complicated exfoliative rejection in pediatric intestinal recipients.

Complications of ER contribute significantly to morbidity and mortality following intestinal transplantation. The surgical management of three pediatric patients who experienced complications of late ER after composite LSB transplantation is described, highlighting the potential for allograft salvage after limited surgical resection. A retrospective case series was compiled. Data collected included time to ER from transplant, medical management of ER, complications, and surgical management of ER complications. All patients had undergone composite LSB transplantation between one and two yr of age. Time to ER after transplantation was 9.5-26.5 months. ER complications included ileal allograft stricture, intramural hematoma with perforation of jejunal allograft, and massive GI hemorrhage secondary to focal ulceration and pseudopolyp formation. With evidence of mucosal regeneration, all three patients underwent limited segmental allograft resection. Two patients continue to maintain satisfactory allograft function 39-44 months following operation. The third patient retained adequate allograft function until he developed PTLD, subsequently dying from disseminated Adenovirus infection 51 months after resection. Severe disruption of intestinal allograft integrity in ER can lend itself to medically refractory complications. Prompt recognition and surgical correction of complications can play a crucial role in allograft salvage and patient survival after ER.

Increased Anti-Flagellin and Anti-Lipopolysaccharide Immunoglobulins in Pediatric Intestinal Failure: Associations With Fever and Central Line-Associated Bloodstream Infections.

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.

Micronutrient deficiencies in pediatric and young adult intestinal transplant patients.

Intestinal transplant recipients are at risk of micronutrient deficiency due to the slow process of post-transplant adaptation. Another contributing factor is calcineurin inhibitor-induced renal tubular dysfunction. Patients are typically supplemented with micronutrients during PN; however, the risk of deficiency may persist even after a successful transition to FEN. The goal was to determine the prevalence of, and associated risk factors for, iron, zinc, magnesium, phosphorus, selenium, copper, folate, and vitamins A, D, E, and B12 deficiency in pediatric intestinal transplant recipients after successful transition to FEN. A retrospective review of prospectively collected data from children who underwent intestinal transplantation at Cincinnati Children's Hospital Medical Center was done. Deficiencies of various micronutrients were defined using the hospital reference values. Twenty-one intestinal transplant recipients, aged one to 23 yr, who were successfully transitioned to FEN were included in the study. The prevalence of micronutrient deficiency was 95.2%. The common deficient micronutrients were iron (94.7%) and magnesium (90.5%). Age ≤ 10 yr (p = 0.002) and tube feeding (p = 0.02) were significant risk factors for micronutrient deficiencies. Pediatric intestinal transplant recipients have a high risk of micronutrient and mineral deficiencies. These deficiencies were more common among younger patients and those who received jejunal feeding.

Multiple micronutrient deficiencies among patients with intestinal failure during and after transition to enteral nutrition.

OBJECTIVES: To determine the prevalence of deficiencies of specific micronutrients (iron, zinc, magnesium, phosphorus, selenium, copper, folate, and vitamins A, D, E, and B12) in children with intestinal failure (IF), and to identify risk factors associated with developing these deficiencies. STUDY DESIGN: This study was a retrospective review of prospectively collected data from 178 children with IF managed by the Intestinal Care Center of Cincinnati Children's Hospital Medical Center between August 1, 2007, and July 31, 2012. Transition to full enteral nutrition (FEN) was defined as the period during which the patient received between 20% and 100% of estimated required nutrition enterally. FEN was defined as the patient's ability to tolerate 100% estimated required nutrition enterally for >2 weeks. RESULTS: Necrotizing enterocolitis was the most common cause of IF (27.5%). Iron was the most common micronutrient deficiency identified both during (83.9%) and after (61%) successful transition to FEN, with a significant reduction in the percentage of patients with iron deficiency between these 2 periods (P = .003). Predictors of micronutrient deficiency after successful transition to FEN included birth weight (P = .03), weight percentile (P = .02), height percentile (P = .04), and duration of parenteral nutrition (PN) (P = .013). After multivariate adjustments, only duration of PN remained statistically significant (P = .03). CONCLUSION: Micronutrient deficiencies persist in patients with IF during and after transition to FEN. These data support the need for routine monitoring and supplementation of these patients, especially those on prolonged PN.

Nutrition management of infants with surgical short bowel syndrome and intestinal failure.

Appropriate nutrition recommendations are important for the successful management of the infant with an injured gastrointestinal tract postsurgery who is at risk for intestinal failure. Management strategies that can be used to augment successful adaptation and prevent liver disease are summarized in this review. These include appropriate postoperative fluid and electrolyte management, modification of parenteral nutrition to minimize intestinal failure-associated liver disease, early and aggressive enteral feeding advancement, the use of hormonal and trophic agents, prevention of central line-associated bloodstream infections using ethanol lock, appropriate treatment, and prevention of pathologic small bowel bacterial overgrowth.