Patrick J. Javid

Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease.

Prolonged use of total parenteral nutrition can lead to nonalcoholic fatty liver disease, ranging from hepatic steatosis to cirrhosis and liver failure. It has been demonstrated that omega-3 fatty acids are negative regulators of hepatic lipogenesis and that they can also modulate the inflammatory response in mice. Furthermore, they may attenuate hepatic steatosis even in leptin-deficient ob/ob mice. We hypothesized that omega-3 fatty acid supplementation may protect the liver against hepatic steatosis in a murine model of parenteral nutrition in which all animals develop steatosis and liver enzyme disturbances. For testing this hypothesis, groups of mice received a fat-free, high-carbohydrate liquid diet ad libitum for 19 d with enteral or i.v. supplementation of an omega-3 fatty acid emulsion or a standard i.v. lipid emulsion. Control mice received food alone or the fat-free, high-carbohydrate diet without lipid supplementation. Mice that received the fat-free, high-carbohydrate diet only or supplemented with a standard i.v. lipid emulsion developed severe liver damage as determined by histology and magnetic resonance spectroscopy as well as elevation of serum liver function tests. Animals that received an i.v. omega-3 fatty acid emulsion, however, showed only mild deposits of fat in the liver, whereas enteral omega-3 fatty acids prevented hepatic pathology and led to normalization of liver function tests. In conclusion, whereas standard i.v. lipid emulsions fail to improve dietary-induced steatotic injury to the liver, i.v. supplementation of omega-3 fatty acids partially and enteral supplementation completely protects the liver against such injury.

Serial Transverse Enteroplasty Enhances Intestinal Function in a Model of Short Bowel Syndrome

Objective/Summary Background Data:Serial transverse enteroplasty (STEP) is a new intestinal lengthening procedure that has been shown to clinically increase bowel length. This study examined the impact of the STEP procedure upon intestinal function in a model of short bowel syndrome. Methods:Young pigs (n = 10) had a reversed segment of bowel interposed to induce bowel dilatation. Five pigs underwent a 90% bowel resection with a STEP procedure on the remaining dilated bowel while 5 served as controls and had a 90% bowel resection without a STEP procedure. Determinations of nutritional status, absorptive capacity, and bacterial overgrowth were conducted 6 weeks after resection. Statistical comparisons were made by 2-sample t test (significance at P < 0.05). Results:The STEP procedure lengthened the bowel from 105.2 ± 7.7 cm to 152.2 ± 8.3 cm (P < 0.01). The STEP animals showed improved weight retention compared with controls (mean, −0.5% ± 1.8% body weight versus −17.6% ± 1.5%, P < 0.001). Intestinal carbohydrate absorption, as measured by d-Xylose absorption and fat absorptive capacity as measured by serum vitamin D and triglyceride levels, were increased in the STEP group versus controls. Serum citrulline, a marker of intestinal mucosal mass, was significantly elevated in the STEP pigs compared with controls. None of the STEP animals but 4 of 5 control animals were noted to have gram-negative bacterial overgrowth in the proximal bowel. Conclusions:STEP improves weight retention, nutritional status, intestinal absorptive capacity, and serum citrulline levels in a porcine short bowel model. A salutary effect upon bacterial overgrowth was also noted. These data support the use of this operation in short bowel syndrome.

The experience of a regional pediatric intestinal failure program: successful outcomes from intestinal rehabilitation.

BACKGROUND The aim of this study was to evaluate the clinical experience of a regional multidisciplinary intestinal failure program for children established in 2005. METHODS Data were collected from a prospective internal database. Univariate analyses were performed to compare pre- and post-treatment outcomes. Median values are reported. RESULTS Forty-nine children were referred at an age of 7 months. Remnant small bowel length was 29 cm. With follow-up of 14 months, overall patient survival was 88%. Thirteen bowel-lengthening procedures were performed, thereby increasing small bowel length from 83 to 132 cm (P < .05). Enteral autonomy was achieved in 22 patients (45%), and the caloric requirement for parenteral nutrition was decreased from 100% to 41% (P < .01). Conjugated bilirubin was reduced from 4.1 to 0 mg/dL (P < .05). CONCLUSION A multidisciplinary approach to pediatric intestinal failure that prioritizes intestinal rehabilitation can achieve successful enteral feeding advancement, improved liver function, and excellent survival in intermediate-range follow-up.

The effect of lipid restriction on the prevention of parenteral nutrition-associated cholestasis in surgical infants

PURPOSE Surgical infants requiring long-term parenteral nutrition (PN) are at risk for parenteral nutrition-associated liver disease (PNALD). The purpose of this study was to determine the effect of a lipid restricted PN regimen in preventing the development of PNALD in surgical infants. METHODS In 2009, we implemented a lipid restricted strategy in surgical infants expected to be on long-term PN using a soy-based lipid emulsion at a goal provision of 1g/kg/day throughout a patients entire PN course. An experimental cohort of surgical infants treated with lipid restriction from 2009 to 2011 (n=82) was retrospectively compared to a control cohort of infants from 2005 to 2008 receiving standard intravenous lipid dosing (n=132). A multivariable relative risk regression model was constructed analyzing the association between lipid restriction and PNALD. RESULTS Patients admitted during the lipid restriction era had reduced daily lipid provisions compared to the control group (p<0.001). There were no significant differences in demographic or measured clinical characteristics between the two groups. A significant reduction in the incidence of PNALD was demonstrated in the lipid restricted group compared to the control group (22% vs. 43%, p=0.002). On multivariable relative risk regression, patients treated with standard lipid provisions were 1.77 times more likely to develop PNALD than patients who were lipid restricted (95% CI: 1.2-2.7; p=0.007). CONCLUSION Restriction of intravenous soy-based lipid in PN-fed surgical infants is associated with a reduction in the incidence of liver disease. Early lipid restriction should be considered in all surgical infants who require PN as a preventative measure against PNALD.

The Effect of Insulin Infusion Upon Protein Metabolism in Neonates on Extracorporeal Life Support

Objective:Critically ill neonates on extracorporeal life support (ECLS) demonstrate elevated rates of protein breakdown that, in turn, are associated with increased morbidity and mortality. This study sought to determine if the administration of the anabolic hormone insulin improved net protein balance in neonates on ECLS. Methods:Twelve parenterally fed neonates, on ECLS, were enrolled in a randomized, prospective, crossover trial. Subjects were administered a hyperinsulinemic euglycemic clamp and a control saline infusion. Protein metabolism was quantified using ring-D5-phenylyalanine and ring-D2-tyrosine stable isotopic infusions. Statistical comparisons were made by paired sample t tests (significance at P < 0.05). Results:Serum insulin concentration increased 20-fold during insulin infusion compared with saline infusion control (P < 0.0001). Protein breakdown was significantly decreased during insulin infusion compared with controls (7.98 ± 1.82 vs. 6.89 ± 1.03 g/kg per day; P < 0.05). Serum amino acid concentrations were significantly decreased by insulin infusion (28,450 ± 9270 vs. 20,830 ± 8110 μmol/L; P < 0.02). Insulin administration tended to decrease protein synthesis (9.58 ± 2.10 g/kg per day vs. 8.60 ± 1.20; P = 0.05). For the whole cohort, insulin only slightly improved net protein balance (protein synthesis minus protein breakdown) (1.60 ± 0.80 vs. 1.71 ± 0.89 g/kg per day; P = 0.08). In neonates receiving ≥2 g/kg per day of dietary amino acids insulin significantly improved net protein balance (2.17 ± 0.34 vs. 2.40 ± 0.26 g/kg per day; P < 0.01). Conclusions:Insulin effectively decreases protein breakdown in critically ill neonates on ECLS. However, this is associated with a significant reduction in plasma amino acids and a trend toward decreased protein synthesis. Insulin administration significantly improves net protein balance only in those ECLS neonates in whom adequate dietary protein is provided.

Selenium Deficiency in Pediatric Patients With Intestinal Failure as a Consequence of Drug Shortage

BACKGROUND Parenteral nutrition (PN) is a lifesaving therapy for children with intestinal failure and can now be used chronically without the life-threatening complications of the past. Adequate intravenous trace element supplementation is required as part of a complete nutrition prescription. According to the U.S. Food and Drug Administration (FDA), the number of drug shortages, including sterile injectable agents used as PN components, has increased since 2010. Selenious acid as an individual additive was recently unavailable at our institution for 9 months due to a national shortage. MATERIALS AND METHODS To assess the impact of the selenious acid shortage, we retrospectively compiled data from existing clinical records for eligible patients. We included children with intestinal failure on full PN support who were older than 1 year at the onset of the selenium shortage. Whole-blood selenium concentrations prior to the selenious acid shortage were compared with concentrations drawn during the shortage. RESULTS Five patients with intestinal failure and complete PN dependence were identified, and all 5 patients had normal serum selenium concentrations prior to the shortage. All 5 patients developed severe biochemical selenium deficiency in direct correlation with the shortage of selenium. No morbidity associated with selenium deficiency was observed. Selenium concentrations recovered after selenium supplementation was reinstituted. CONCLUSION A national selenious acid shortage was associated with biochemical selenium deficiency in a cohort of children with intestinal failure. Despite very low selenium concentrations, none of our patients exhibited clinical signs of deficiency.

A contemporary analysis of parenteral nutrition-associated liver disease in surgical infants

BACKGROUND/PURPOSE Despite advances in pediatric nutritional support and a renewed focus on management of intestinal failure, there are limited recent data regarding the risk of parenteral nutrition (PN)-associated liver disease in surgical infants. This study investigated the incidence of cholestasis from PN and risk factors for its development in this population. METHODS A retrospective review was performed of all neonates in our institution who underwent abdominal surgery and required postoperative PN from 2001 to 2006. Cholestasis was defined as 2 conjugated bilirubin levels greater than 2 mg/dL over 14 days. Nonparametric univariate analyses and multivariate logistic regression were used to model the likelihood of developing cholestasis. Median values with range are presented. RESULTS One hundred seventy-six infants met inclusion criteria, and patients received PN for 28 days (range, 2-256 days). The incidence of cholestasis was 24%. Cholestatic infants were born at an earlier gestational age (34 vs 36 weeks; P < .01), required a 3-fold longer PN duration (76 vs 21 days; P < .001), had longer inpatient stays (86 vs 29 days; P < .001), and were more likely to be discharged on PN. The median time to cholestasis was 23 days. Cholestasis was an early development; 77% of cholestatic infants developed cholestasis by 5 weeks of PN exposure. On multivariate regression, only prematurity was significantly associated with development of cholestasis (P < .05). CONCLUSION In this analysis, the development of PN-associated liver disease occurred early in the course of exposure to PN. These data help to define the time course and prognosis for PN-associated cholestasis in surgical infants.

Ultrashort bowel syndrome in children.

Objective: Recent data have demonstrated improved survival in children with intestinal failure. We hypothesized that this trend would also be observed in children with ultrashort bowel syndrome. Methods: A prospective database from Seattle Childrens Intestinal Failure Program was used to evaluate outcomes and morbidities of consecutive patients with 10 cm or less of small bowel enrolled in the program since 2005. Data are listed as median (range). Results: Five patients were identified with a bowel length of 6 (1–10) cm and follow-up of 54 (43–61) months. All children have survived and are currently between 3.5 and 5.5 years of age. One patient underwent isolated intestinal transplantation and one patient is currently listed for intestinal transplantation. The transplanted child is fully enterally fed. The other patients remain at least partially dependent on parenteral nutrition. None of these patients have current evidence of parenteral nutrition-associated liver disease. Patients have required extensive care after referral to our program, including 18 (15–32) visits to the emergency room, 152 (114–273) days of inpatient care, and 6 (5–9) central line–associated blood stream infections. Conclusions: Long-term survival in children with ultrashort bowel length is possible after referral to an intestinal failure program, although extensive medical management is required. These children may be reasonable candidates for long-standing intestinal rehabilitation as a bridge to intestinal transplantation.

Hidden Attraction: A Menacing Meal of Magnets and Batteries

BACKGROUND Magnet and button battery ingestions are increasingly common, and can result in significant morbidity. Timely identification of hazardous foreign body ingestions can be difficult in non-verbal and non-disclosing children. OBJECTIVES We aim to present a case that demonstrates some of the challenges around identifying and correctly locating magnets and batteries, and the importance of prompt identification and removal. CASE REPORT We describe an older child with the covert ingestion of multiple magnets and batteries, with magnets that attracted across the stomach and a loop of jejunum. Mild symptoms and signs resulted in a delayed diagnosis and serious consequences. Radiographs suggested a gastric location of the foreign bodies. CONCLUSION Health care workers should consider the possibility of battery or magnet ingestions in children with vomiting and abdominal pain, even when well-appearing. Like esophageal batteries, multiple gastrointestinal magnets and combined magnet-battery ingestions can cause significant morbidity, and prompt identification is important. Providers should ask verbal children for ingestion histories, and consider radiographs when symptoms are atypical or persistent. Like esophageal batteries, gastrointestinal magnet-battery ingestions should be removed promptly to prevent complications. Caregivers should supervise or limit the use of toys that include magnets and batteries.

The optimal timing of referral to an intestinal failure program: the relationship between hyperbilirubinemia and mortality

PURPOSE Multidisciplinary treatment of pediatric intestinal failure has shown promising results. However, there are limited data as to the optimal time frame for referral of patients to intestinal failure programs. The aim of this study was to explore the relationship of hyperbilirubinemia at referral with patient outcomes in a multidisciplinary program. METHODS A retrospective analysis was performed of a prospectively collected database from a multidisciplinary intestinal failure program. Multivariable logistic regression adjusted for age at referral was used to model the association between the conjugated bilirubin at referral and risk of mortality. Median values with range are reported. RESULTS Sixty-two patients were referred from 2005 to 2009. Patients presented at age 6.4 months (0.4-261.4 months) and were followed up for 16.8 (0.3-53.0) months. Nine subjects (14.5%) died, and 12 subjects (19.4%) were listed for combined liver-intestine transplant. A 50% mortality was seen in patients referred with a conjugated bilirubin ≥ 7.2 mg/dL (n = 12), whereas mortality at referral bilirubin levels <7.2 mg/dL was 6%. After adjusting for age at referral, patients with a conjugated bilirubin ≥ 7.2 mg/dL at referral were 15.4 times more likely to die than patients who presented with lower bilirubin levels (P = .001; 95% confidence interval, 2.8-83.4). CONCLUSION Within a pediatric intestinal failure program, mortality is associated with the degree of hyperbilirubinemia at time of referral. These data strongly suggest that these patients should be referred to a multidisciplinary program early in the evolution of their liver disease.