Paul W. Wales

Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome.

Background: Parenteral omega-3 fatty acids, such as Omegaven, may benefit patients with pediatric short bowel syndrome (SBS) who develop parenteral nutrition–associated liver disease (PNALD). Patients and Methods: Retrospective cohort describing the outcome of all 12 children with SBS and advanced PNALD who were treated with Omegaven (target omega-6 to omega-3 fatty acid ratio = 1:1 to 2:1). Results: The median age was 7.5 (range 3.6–46) months, and median parenteral nutrition duration before starting Omegaven was 28.4 (range 15.3–55.3) weeks. Median initial serum conjugated bilirubin was 137 (range 54–203) μmol/L (8.06 [3.18–11.94] mg/dL). Of the 12 patients, 9 had complete and sustained resolution of hyperbilirubinemia within a median of 24 (range 7–37) weeks, and all are no longer being considered for liver transplantation. Improvements in markers of hepatic inflammation as well as nutritional status also were noted in these patients. Three patients received a liver-intestine transplant while taking Omegaven. There were no complications attributable to Omegaven. Conclusions: Omegaven is associated with restoration of liver function in patients with SBS and advanced liver disease. Parenteral omega-3 fatty acids, such as Omegaven, have the potential to fundamentally alter the paradigm of neonatal SBS from one of early death or transplantation from liver failure to a more chronic disease. More children with SBS should achieve full enteral tolerance and those who do not have the capacity for intestinal adaptation should be able to survive and receive an intestinal graft when older.

Natural History of Pediatric Intestinal Failure: Initial Report from the Pediatric Intestinal Failure Consortium

OBJECTIVE To characterize the natural history of intestinal failure (IF) among 14 pediatric centers during the intestinal transplantation era. STUDY DESIGN The Pediatric Intestinal Failure Consortium performed a retrospective analysis of clinical and outcome data for a multicenter cohort of infants with IF. Entry criteria included infants <12 months receiving parenteral nutrition (PN) for >60 continuous days. Enteral autonomy was defined as discontinuation of PN for >3 consecutive months. Values are presented as median (25th, 75th percentiles) or as number (%). RESULTS 272 infants with a gestational age of 34 weeks (30, 36) and birth weight of 2.1 kg (1.2, 2.7) were followed for 25.7 months (11.2, 40.9). Residual small bowel length in 144 patients was 41 cm (25.0, 65.5). Diagnoses were necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), combinations of these diagnoses (46, 17%), aganglionosis (11, 4%), and other single or multiple diagnoses (48, 18%). Prescribed medications included oral antibiotics (207, 76%), H2 blockers (187, 69%), and proton pump inhibitors (156, 57%). Enteral feeding approaches varied among centers; 19% of the cohort received human milk. The cohort experienced 8.9 new catheter-related blood stream infections per 1000 catheter days. The cumulative incidences for enteral autonomy, death, and intestinal transplantation were 47%, 27%, and 26%, respectively. Enteral autonomy continued into the fifth year after study entry. CONCLUSIONS Children with IF endure significant mortality and morbidity. Enteral autonomy may require years to achieve. Improved medical, nutritional, and surgical management may reduce time on PN, mortality, and need for transplantation.

Establishing norms for intestinal length in children.

BACKGROUND Existing data on pediatric intestinal length (IL) are limited because most studies report postmortem values. Using prospective data, appropriate norms for IL were developed. METHOD The IL measurements, using a silk suture on the antimesenteric border, were prospectively made on patients between 24 weeks of gestational age and 5 years of age undergoing laparotomy. Patients with gastrointestinal malformations or those above or below 2 SDs for growth parameters were excluded. A curve fitting process was applied to determine the best model for IL (small bowel and colon separately) from among postconception age, weight, and height at surgery. RESULTS One hundred eight patients participated in this study. Highly predictive (R(2) > 0.8) models for IL were determined for all predictor variables (postconception age, weight, and height) examined suggesting that all of these variables are excellent predictors determinants of IL. Although all models had statistically similar properties, the model using height had the best performance across the full range of the variable. CONCLUSION Although age, weight, nor height was definitely superior for the prediction of IL, we propose that until external validations of our models occur, height at surgery be used for the prediction of expected small intestinal and colon length in infants.

Ethanol Locks to Prevent Catheter-Related Bloodstream Infections in Parenteral Nutrition: A Meta-Analysis

OBJECTIVE: Patients with pediatric intestinal failure (IF) depend on parenteral nutrition for growth and survival, but are at risk for complications, such as catheter-related bloodstream infections (CRBSIs). CRBSI prevention is crucial, as sepsis is an important cause of IF-associated liver disease and mortality. We aim to estimate the pooled effectiveness and safety of ethanol locks (ELs) in comparison with heparin locks (HLs) with regard to CRBSI rate and catheter replacements for pediatric IF patients with chronic parenteral nutrition dependence. METHODS: A systematic review without language restriction was performed on Medline (1948–2010), Embase (1980–2010), and conference programs and trial registries up to December 2010. Search terms included “Catheter-Related Infections,” “Catheter,” “Catheters, Indwelling,” “alcohol,” “ethanol,” and “lock.” Two authors identified 4 retrospective studies for the pediatric IF population. Double, independent data extraction using predefined data fields and risk of bias assessment (Newcastle-Ottawa scale) was performed. RESULTS: In comparison with HLs, ELs reduced the CRBSI-rate per 1000 catheter days by 7.67 events and catheter replacements by 5.07. EL therapy decreased the CRBSI rate by 81% and replacements by 72%. One hundred eight to 150 catheter days of EL exposure were necessary to prevent 1 CRBSI and 122 to 689 days of exposure avoided 1 catheter replacement. Adverse events were rare and included thrombotic events. CONCLUSIONS: In pediatric patients with IF, EL is a more effective alternative to HL. Adverse events include thrombotic events.

Short bowel syndrome: epidemiology and etiology

Pediatric short bowel syndrome (SBS) is most commonly caused by congenital or acquired conditions of the newborn. SBS is associated with an inability of the bowel to adequately absorb water and nutrients in sufficient quantities to meet caloric, fluid, and electrolyte demands, thus necessitating dependence on parenteral nutrition (PN). It is this dependence on PN, that is responsible for the majority of morbidity and mortality associated with SBS, including central venous catheter infections and PN-induced cholestatic liver dysfunction. There are very few estimates of SBS incidence and mortality in the literature. The epidemiology of SBS is reviewed and the limitations of the published literature are discussed.

Ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients with intestinal failure: preliminary experience☆

BACKGROUND Catheter-related bloodstream infections (CRBSI) cause morbidity and mortality in patients with intestinal failure dependent on parenteral nutrition. Ethanol lock of central venous catheters may decrease CRBSI, but limited pediatric data are available. METHODS Home parenteral nutrition patients with at least one previous CRBSI were initiated on a 70% ethanol lock protocol for a minimum of 4 hours. Infection rates (per 1000 catheter days) before and after initiation of ethanol locks were compared using a paired t test. RESULTS Ten patients (4 girls; median age, 44 months [range, 31-129 months]) began ethanol lock therapy after a total of 91 CRBSIs (37 gram-positive, 30 gram-negative, and 24 fungal) with a mean of 10.2 ± 6.2 per 1000 catheter days. Patients received ethanol lock for an average of 227 ± 64 days with only 3 CRBSI occurring (CRBSI rate of 0.9 ± 1.8 per 1000 catheter days [P = .005]). Central venous catheter replacements decreased from 5.6 per 1000 days to 0.3 per 1000 days posttherapy (P = .038). Ethanol lock was discontinued in 2 of 10 patients because of catheter thrombosis. CONCLUSION Preliminary results demonstrate a significant decrease in CRBSI with a 70% ethanol lock protocol. Catheter thrombosis may be a limitation that needs to be addressed. With such a dramatic therapeutic effect, a randomized trial is feasible and should be performed.

Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease

BACKGROUND & AIMS Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children younger than 6 years of age. They have been associated with several gene variants. Our aim was to identify the genes that cause VEOIBD. METHODS We performed whole exome sequencing of DNA from 1 infant with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines. RESULTS We identified compound heterozygote mutations in the Tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected TTC7A mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B to regulate phosphatidylinositol 4-kinase at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. Phosphatidylinositol 4-kinase was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased apoptosis, and decreased production of phosphatidylinositol 4-phosphate. CONCLUSIONS In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the phosphatidylinositol 4-kinase-TTC7A-EFR3 homolog B pathway are involved in the pathogenesis of VEOIBD.

Intermediate outcomes after serial transverse enteroplasty in children with short bowel syndrome

AIM The aim of this study is to report 5-year outcomes in patients who have received serial transverse enteroplasty (STEP) using clinical and biochemical assessments of intestinal function. METHODS Thirty-one STEP procedures have been performed at our institution. Twelve patients who received STEP before January 2005 were analyzed. Clinical and biochemical outcomes were performed pre-STEP and post-STEP on an annual basis. Paired t tests were used to compare post-STEP outcomes to pre-STEP values (P < .05 was significant). MAIN RESULTS There were 12 patients (3 females; median age, 5.5 months). Serial transverse enteroplasty resulted in mean increase in length of dilated bowel segment of 89% ± 26% and increase in total small bowel length of 46% ± 40%. Two patients received liver-intestinal transplants post-STEP (at 4 and 5 months), and 2 patients died of liver failure at 3 and 8 months. The remaining 8 of 12 patients all show stable intestinal absorptive capacity (data not shown). Of 8 patients, 7 were weaned off parenteral nutrition by 4 years. No patient has required repeat STEP or bowel tapering. Two patients developed staple line leak, and 1 patient developed gastrointestinal bleed from staple line ulcers. CONCLUSION This report represents the largest series of STEP patients followed up beyond 5 years. Long-term clinical, biochemical, and radiologic outcomes appear to be robust.

Comparison of the Nuss and the Ravitch procedure for pectus excavatum repair: a meta-analysis.

PURPOSE Pectus excavatum is the most common chest wall deformity in children. Two procedures are widely applied-the Nuss and the Ravitch. Several comparative studies are published evaluating both procedures with inconsistent results. Our objective was to compare the Nuss procedure to the Ravitch procedure using systematic review and meta-analysis methodology. METHODS All publications describing both interventions were sought through the Cochrane Central Register of Controlled Trials (CENTRAL) database, MEDLINE, and EMBASE. The statistical analysis was performed using RevMan 5 software. Odds ratios (OR) and weighted mean differences (WMDs) with 95% confidence intervals are presented. RESULTS No randomized trials were identified. Nine prospective and retrospective studies were identified and were included in this study. There was no significant difference in overall complication rates between both techniques (OR, 1.75 (0.62-4.95); P = .30). Looking at specific complications, the rate of reoperation because of bar migration or persistent deformity was significantly higher in the Nuss group (OR, 5.68 (2.51-12.85); P = .0001). Also, postoperative pneumothorax and hemothorax were higher in the Nuss group (OR, 6.06 [1.57-23.48]; P = .009 and OR, 5.60 [1.00-31.33]; P = .05), respectively. Duration of surgery was longer with the Ravitch (WMD, 69.94 minutes (0.83-139.04); P = .05). There was no difference in length of hospital stay (WMD, 0.4 days (-2.05 to 2.86); P = .75) or time to ambulation after surgery (WMD, 0.33 days [-0.89 to 0.23]; P = .24). Among studies looking at patient satisfaction, there was no difference between both techniques. CONCLUSIONS Our results suggest no differences between the Nuss procedure vs the Ravitch procedure with respect to overall complications, length of hospital stay, and time to ambulation. However, the rate of reoperation, postoperative hemothorax, and pneumothorax after the Nuss procedure were higher compared to the Ravitch procedure. No studies showed a difference in patient satisfaction.

Routine use of a SILASTIC spring-loaded silo for infants with gastroschisis: a multicenter randomized controlled trial.

BACKGROUND Retrospective studies have suggested that routine use of a preformed silo for infants with gastroschisis may be associated with improved outcomes. We performed a prospective multicenter randomized controlled trial to test this hypothesis. METHODS Eligible infants were randomized to (1) routine bedside placement of a preformed Silastic spring-loaded silo, with gradual reduction and elective abdominal wall closure, or (2) primary closure. RESULTS There were 27 infants in each group. There was no significant difference between groups with respect to age, weight, sex, Apgar scores, prenatal diagnosis, or mode of delivery. The total number of days on the ventilator was lower in the spring-loaded silo group, although it did not reach statistical significance (3.2 vs 5.3, P = .07). There was no significant difference between groups with respect to length of time on total parenteral nutrition, length of stay, or incidence of sepsis and necrotizing enterocolitis. CONCLUSION Routine use of a preformed silo was associated with similar outcomes to primary closure for infants with gastroschisis but with a strong trend toward fewer days on the ventilator. Use of a preformed silo has the advantage of permitting definitive abdominal wall closure in a more elective setting.