Neonates with short bowel syndrome: an optimistic future for parenteral nutrition independence.

IMPORTANCE: The introduction of hepatoprotective strategies and multidisciplinary management has significantly improved the outcome of neonates with short bowel syndrome (SBS) who require parenteral nutrition (PN). OBJECTIVE: To determine the probability of weaning from PN based on intestinal length in neonates with SBS amidst the new era of hepatoprotective strategies and multidisciplinary management. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review at a single-center academic institution. Neonates with no more than 100 cm of small intestine at a corrected gestational age of no more than 30 days who were diagnosed with a surgical gastrointestinal disease and PN dependent for at least 2 weeks were included. Data were collected from January 1, 2004, through June 1, 2012. EXPOSURE: Neonates with SBS requiring PN. MAIN OUTCOMES AND MEASURES: The probability of wean from PN without reinitiation for at least 1 year, as determined by logistic regression. Predictors of wean were evaluated using exact conditional logistic regression. Predictors of time to wean were determined by Cox proportional hazards regression. RESULTS: Sixty-three patients with a median (25th percentile, 75th percentile [interquartile range (IQR)]) gestational age of 31 (27, 35) weeks, birth weight of 1423 (895, 2445) g, small intestinal length of 41.0 (24.0, 65.0) cm, and predicted length of 29.0% (17.1%, 45.5%) underwent analysis. Fifty-one patients (81%) received a fish oil-based lipid emulsion (1 g/kg/d), 40 (63%) were weaned, 11 (17%) remained PN dependent, 4 (6%) underwent transplant, and 8 (13%) died while on PN. Excluding patients who underwent transplant or died, the median (IQR) small intestinal length was 55.0 (28.0, 75.0) cm in weaned and 26.0 (14.0, 41.0) cm in PN-dependent patients (P = .006), with 40 of 51 (78%) weaned by study end. The cumulative probability of wean for patients with at least 50 cm of small intestine was 88% after 12 and 96% after 24 months. Patients with less than 50 cm of small intestine had a cumulative probability of wean of 23% after 12, 38% after 24, and 71% after 57 months. Small intestinal length was found to be the primary predictor of wean. Notable predictors of time to wean included the amount of small intestine remaining (hazard ratio, 1.94 [95% CI, 1.45-2.58] per 20 cm of intestine; P < .001), entirety of care within our institution (3.27 [1.59-6.72]; P = .001), and intestinal lengthening procedure (0.19 [0.04-0.84]; P = .03). CONCLUSIONS AND RELEVANCE: The majority of patients will wean from PN despite short intestinal length, likely as a result of new management strategies combined with a multidisciplinary team approach.

The effect of docosahexaenoic acid on bone microstructure in young mice and bone fracture in neonates.

BACKGROUND: As low bone mineral density is a risk factor for fracture in childhood, optimizing age appropriate bone mass is recommended and might lower the impact of bone loss related to age. Consumption of omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic and docosahexaenoic (DHA) acids have been shown to beneficially modulate bone metabolism. The objective of this study was to determine the incidence of fracture in neonates receiving a fish compared with soybean oil-based intravenous lipid emulsion and evaluate the effect of varying dietary omega-3 PUFA consumption on growing bone in young mice. MATERIALS AND METHODS: Eligibility criteria for the clinical study included gestational age ≤37 wk and parenteral nutrition-dependence for ≥4 wk. Radiographs were reviewed after lipid initiation to identify radiologic bone fracture. The animal study evaluated female C57/Bl6 mice randomized into one of five groups from age 3-12 wk, at which time femurs were harvested for micro-computed tomography and light microscopy analysis. RESULTS: A lower incidence of bone fracture was found in neonates maintained on fish compared with soybean oil. In the animal study, findings suggest the DHA diet provides the best protection against trabecular bone loss as evidenced by increased bone volume fraction, increased trabecular number, and decreased trabecular separation on micro-computed tomography. These protective effects appeared to affect the bone microstructure alone. CONCLUSIONS: The lower fracture risk observed in fish oil fed neonates in combination with the protective effects of DHA observed in the femurs of young C57/BL6 mice suggest an important role for omega-3 PUFAs on bone growth.

A comparison of 2 intravenous lipid emulsions: interim analysis of a randomized controlled trial.

OBJECTIVE: To assess the safety and efficacy of a fish oil-based intravenous fat emulsion (FIFE) in reducing the incidence of cholestasis in neonates compared with the traditional soybean oil-based intravenous fat emulsion (SIFE). METHODS: A double-blind randomized controlled trial was conducted. Nineteen neonates were enrolled (10 SIFE; 9 FIFE). Nutrition assessments and laboratory studies were serially obtained for the duration of PN support or until 6 months' corrected gestational age. Neurodevelopmental outcomes were assessed at 6 and 24 months' corrected age. RESULTS: There were no differences between groups in demographic characteristics, with an overall median age of 2 days, gestational age of 36 weeks, and birth weight of 2410 g. There were no differences between groups in baseline laboratory values other than alkaline phosphatase (lower in the FIFE group) or in the duration of parenteral nutrition (PN), amount of enteral intake, or the number of operative procedures. The incidence of cholestasis among enrolled patients was significantly lower than expected, resulting in early study termination and an inability to assess for differences in the incidence of cholestasis. The FIFE was associated with no increased risk of growth impairment, coagulopathy, infectious complications, hypertriglyceridemia, or adverse neurodevelopmental outcomes. No patient developed essential fatty acid deficiency. CONCLUSION: The FIFE at 1 g/kg/d was well tolerated in the neonates recruited for this study. Given the necessary early termination of this study, a follow-up trial with revised eligibility criteria is necessary to determine whether the provision of FIFE decreases the incidence of PN-cholestasis compared with the traditional SIFE.

A.S.P.E.N. clinical guidelines: nutrition support of neonatal patients at risk for metabolic bone disease.

BACKGROUND: Premature infants are at increased risk for metabolic bone disease, with resulting delayed bone growth, osteopenia, and rickets. METHOD: A systematic review of the best available evidence to answer a series of questions regarding neonatal patients at risk of metabolic bone disease receiving parenteral or enteral nutrition was undertaken and evaluated using concepts adopted from the Grading of Recommendations, Assessment, Development and Evaluation working group. A consensus process was used to develop the clinical guideline recommendations prior to external and internal review and approval by the American Society for Parenteral and Enteral Nutrition Board of Directors. QUESTIONS: (1) What maternal risk factors predispose the neonate to metabolic bone disease? (2) What is the optimal type of feeding to promote neonatal bone health? (3) When and how should vitamin D supplements be administered? (4) Does parenteral nutrition (PN) predispose a neonate to metabolic bone disease, and if so, are there PN formulation recommendations to minimize this risk?

Provision of a soy-based intravenous lipid emulsion at 1 g/kg/d does not prevent cholestasis in neonates.

BACKGROUND: One of the most common and severe complications of long-term parenteral nutrition (PN) is PN-associated cholestasis. The soybean oil-based lipid emulsion administered with PN has been associated with cholestasis, leading to an interest in lipid reduction strategies. The purpose of this study was to determine whether the provision of a soybean oil-based lipid emulsion at 1 g/kg/d compared with 2-3 g/kg/d is associated with a reduced incidence of cholestasis. METHODS: Retrospective review of neonates admitted between 2007 and 2011 with a gastrointestinal condition necessitating ≥ 21 days of PN support. Neonates were divided into 2 groups based on the intravenous lipid emulsion dose: 1-g group (1 g/kg/d) and 2- to 3-g group (2-3 g/kg/d). The primary outcome measure was the incidence of cholestasis. RESULTS: Sixty-one patients met inclusion criteria (n = 29, 1-g group; n = 32, 2- to 3-g group). The 2 groups did not differ in any baseline characteristics other than associated comorbidities that were more common in the 2- to 3-g group. The duration of PN, the number of operative procedures and bloodstream infections, and enteral nutrition (EN) were similar between groups. The incidence of cholestasis was not different between groups (51.7%, 1-g group; 43.8%, 2- to 3-g group; P = .61), and there was no difference between groups in the time to cholestasis (32.6 ± 24.1 days, 1-g group; 27.7 ± 10.6 days, 2- to 3-g group; P = .48). Overall, 44.8% of patients with cholestasis were transitioned to full EN, and 55.2% were transitioned to a fish oil-based lipid emulsion after which the direct bilirubin normalized in all patients. CONCLUSION: Lipid reduction to 1 g/kg/d does not prevent or delay the onset of cholestasis in neonates.

The effect of varying ratios of docosahexaenoic acid and arachidonic acid in the prevention and reversal of biochemical essential fatty acid deficiency in a murine model.

OBJECTIVE: Essential fatty acids (EFA) are necessary for growth, development, and biological function, and must be acquired through the diet. While linoleic acid (LA) and alpha-linolenic acid (ALA) have been considered the true EFAs, we previously demonstrated that docosahexaenoic acid (DHA) and arachidonic acid (AA) taken together as the sole source of dietary fatty acids can prevent biochemical essential fatty acid deficiency (EFAD). This study evaluates the effect of varying dietary ratios of DHA:AA in the prevention and reversal of biochemical EFAD in a murine model. METHODS: Using a murine model of EFAD, we provided mice with 2.1% of daily caloric intake in varying DHA:AA ratios (1:1, 5:1, 10:1, 20:1, 200:1, 100:0) for 19 days in association with a liquid high-carbohydrate fat-free diet to evaluate the effect on fatty acid profiles. In a second experiment, we evaluated the provision of varying DHA:AA ratios (20:1, 200:1, 100:0) on the reversal of biochemical EFAD. RESULTS: Mice provided with DHA and AA had no evidence of biochemical EFAD, regardless of the ratio (1:1, 5:1, 10:1, 20:1, 200:1, 100:0) administered. Biochemical EFAD was reversed with DHA:AA ratios of 20:1, 200:1, and 100:0 following 3 and 5 weeks of dietary provision, although the 20:1 ratio was most effective in the reversal and stabilization of the triene:tetraene ratio. CONCLUSION: Provision of DHA and AA, at 2.1% of daily caloric intake in varying ratios can prevent biochemical evidence of EFAD and hepatic steatosis over the short-term, with a ratio of 20:1 DHA:AA most effectively reversing EFAD.

Prolonging the female reproductive lifespan and improving egg quality with dietary omega-3 fatty acids.

Women approaching advanced maternal age have extremely poor outcomes with both natural and assisted fertility. Moreover, the incidence of chromosomal abnormalities and birth defects increases with age. As of yet, there is no effective and practical strategy for delaying ovarian aging or improving oocyte quality. We demonstrate that the lifelong consumption of a diet rich in omega-3 fatty acids prolongs murine reproductive function into advanced maternal age, while a diet rich in omega-6 fatty acids is associated with very poor reproductive success at advanced maternal age. Furthermore, even short-term dietary treatment with a diet rich in omega-3 fatty acids initiated at the time of the normal age-related rapid decline in murine reproductive function is associated with improved oocyte quality, while short-term dietary treatment with omega-6 fatty acids results in very poor oocyte quality. Thus, omega-3 fatty acids may provide an effective and practical avenue for delaying ovarian aging and improving oocyte quality at advanced maternal age.

A.S.P.E.N. clinical guidelines: nutrition support of neonatal patients at risk for necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most devastating diseases in the neonatal population, with extremely low birth weight and extremely preterm infants at greatest risk. METHOD: A systematic review of the best available evidence to answer a series of questions regarding nutrition support of neonates at risk of NEC was undertaken and evaluated using concepts adopted from the Grading of Recommendations, Assessment, Development and Evaluation working group. A consensus process was used to develop the clinical guideline recommendations prior to external and internal review and approval by the A.S.P.E.N. Board of Directors. RESULTS/ CONCLUSIONS: (1) When and how should feeds be started in infants at high risk for NEC? We suggest that minimal enteral nutrition be initiated within the first 2 days of life and advanced by 30 mL/kg/d in infants ≥ 1, 000 g. (Weak) (2) Does the provision of mother's milk reduce the risk of developing NEC? We suggest the exclusive use of mother's milk rather than bovine-based products or formula in infants at risk for NEC. (Weak) (3) Do probiotics reduce the risk of developing NEC? There are insufficient data to recommend the use of probiotics in infants at risk for NEC. (Further research needed.) (4) Do nutrients either prevent or predispose to the development of NEC? We do not recommend glutamine supplementation for infants at risk for NEC (Strong). There is insufficient evidence to recommend arginine and/or long chain polyunsaturated fatty acid supplementation for infants at risk for NEC. (Further research needed.) (5) When should feeds be reintroduced to infants with NEC? There are insufficient data to make a recommendation regarding time to reintroduce feedings to infants after NEC. (Further research needed.).

Inhibition of neuroblastoma cell proliferation with omega-3 fatty acids and treatment of a murine model of human neuroblastoma using a diet enriched with omega-3 fatty acids in combination with sunitinib.

INTRODUCTION: We investigated the use of dietary omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) in the treatment of neuroblastoma both as a sole agent and in combination with sunitinib, a broad-spectrum tyrosine kinase receptor inhibitor. RESULTS: Substitution of all dietary fat with menhaden oil (ω-3 PUFA rich) resulted in a 40-70% inhibition of tumor growth and a statistically significant difference in the levels of several PUFAs (18:2 ω-6, 20:4 ω-6, 22:4 ω-6, 20:5 ω-3) as compared with a control diet. Furthermore, tumors from animals on the ω-3 fatty acid (FA)-enriched diet had an elevated triene/tetraene ratio suggestive of a change in local eicosanoid metabolism in these tissues similar to that seen with essential fatty acid deficiency. The ω-3 FA-enriched diet also decreased tumor-associated inflammatory cells and induced mitochondrial changes suggestive of mitochondrial damage. Combination treatment with sunitinib resulted in further reduction in tumor proliferation and microvessel density. DISCUSSION: These findings suggest a potential role for ω-3 PUFAs in the combination treatment of neuroblastoma. METHODS: We used a murine model of orthotopic and subcutaneous human neuroblastoma and diets that differ in the FA content to define the optimal dietary ω-3/omega-6 (ω-6) FA ratio required for the inhibition of these tumors.

Docosahexaenoic acid and arachidonic acid prevent essential fatty acid deficiency and hepatic steatosis.

OBJECTIVES: Essential fatty acids are important for growth, development, and physiologic function. α-Linolenic acid and linoleic acid are the precursors of docosahexaenoic and arachidonic acid, respectively, and have traditionally been considered the essential fatty acids. However, the authors hypothesized that docosahexaenoic acid and arachidonic acid can function as the essential fatty acids. METHODS: Using a murine model of essential fatty acid deficiency and consequent hepatic steatosis, the authors provided mice with varying amounts of docosahexaenoic and arachidonic acids to determine whether exclusive supplementation of docosahexaenoic and arachidonic acids could prevent essential fatty acid deficiency and inhibit or attenuate hepatic steatosis. RESULTS: Mice supplemented with docosahexaenoic and arachidonic acids at 2.1% or 4.2% of their calories for 19 days had normal liver histology and no biochemical evidence of essential fatty acid deficiency, which persisted when observed after 9 weeks. CONCLUSION: Supplementation of sufficient amounts of docosahexaenoic and arachidonic acids alone without α-linolenic and linoleic acids meets essential fatty acid requirements and prevents hepatic steatosis in a murine model.

Use of an omega-3 fatty acid-based emulsion in the treatment of parenteral nutrition-induced cholestasis in patients with microvillous inclusion disease.

Microvillous inclusion disease is a congenital intestinal epithelial cell disorder leading to lifelong intestinal failure. In this report, we discuss the use of a fish oil-based lipid emulsion in the treatment of 3 patients with microvillous inclusion disease who developed parenteral nutrition-associated liver disease.

Parenteral fish-oil-based lipid emulsion improves fatty acid profiles and lipids in parenteral nutrition-dependent children.

BACKGROUND: Total parenteral nutrition (PN), including fat administered as a soybean oil-based lipid emulsion (SOLE), is a life-saving therapy but may be complicated by PN-induced cholestasis and dyslipidemia. A fish-oil-based lipid emulsion (FOLE) as a component of PN can reverse PN-cholestasis and has been shown to improve lipid profiles. OBJECTIVE: The objective was to describe changes in the fatty acid and lipid profiles of children with PN-cholestasis who were treated with a FOLE. DESIGN: Lipid and fatty acid profiles of 79 pediatric patients who developed PN-cholestasis while receiving standard PN with a SOLE were examined before and after the switch to a FOLE. All patients received PN with the FOLE at a dose of 1 g · kg(-1) · d(-1) for ≥1 mo. RESULTS: The median (interquartile range) age at the start of the FOLE treatment was 91 (56-188) d. After a median (interquartile range) of 18.3 (9.4-41.4) wk of receiving the FOLE, the subjects' median total and direct bilirubin improved from 7.9 and 5.4 mg/dL to 0.5 and 0.2 mg/dL, respectively (P < 0.0001). Serum triglyceride, total cholesterol, LDL, and VLDL concentrations significantly decreased by 51.7%, 17.4%, 23.7%, and 47.9%, respectively. CONCLUSIONS: The switch from a SOLE to a FOLE in PN-dependent children with cholestasis and dyslipidemia was associated with a dramatic improvement in serum triglyceride and VLDL concentrations, a significant increase in serum omega-3 (n-3) fatty acids (EPA and DHA), and a decrease in serum omega-6 fatty acids (arachidonic acid). A FOLE may be the preferred lipid emulsion in patients with PN-cholestasis, dyslipidemia, or both. This trial is registered at clinicaltrials.gov as NCT00910104.

The prevention and treatment of intestinal failure-associated liver disease in neonates and children.

Intestinal Failure Associated Liver Disease (IFALD) is a common and potentially life-threatening problem for pediatric patients receiving long-term parenteral nutrition (PN). Risk factors for IFALD include premature birth, low birth weight, long-term PN, intestinal stasis and sepsis. Preventative strategies are the cornerstone of improving outcomes in IFALD and include enteral feeding, weaning of PN, reduced dose lipid emulsions and the early recognition and treatment of sepsis. Recent work also demonstrates the efficacy of fish-oil based lipid emulsions in the prevention and treatment of IFALD. Transplantation is an option for end-stage liver disease but is associated with significant morbidity and mortality.

Surgical intervention in the setting of parenteral nutrition-associated cholestasis may exacerbate liver injury.

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.

Prevention of parenteral nutrition-associated liver disease: role of omega-3 fish oil.

PURPOSE OF REVIEW: Parenteral nutrition-associated liver disease (PNALD) is the most severe complication of long-term parenteral nutrition. Its cause remains unclear, although recent studies suggest that the omega-6 polyunsaturated fatty acids in plant oil-based lipid emulsions and the associated phytosterols contribute to the development of hepatotoxicity. In contrast, fish oil-based lipid emulsions are composed mainly of omega-3 polyunsaturated fatty acids and are hypothesized to be hepatoprotective. This review will discuss fish oil-based lipid emulsions in the prevention of PNALD. RECENT FINDINGS: In several animal models of PNALD, the use of an intravenous fish oil-based lipid emulsion improved parenteral nutrition-associated cholestasis without resultant essential fatty acid deficiency or growth impairment. Following these results and preliminary human data, an open trial for compassionate use was initiated, followed by a randomized controlled trial to evaluate the current management of pediatric PNALD. To date, at the author's institution, more than 130 children with PNALD have been treated with Omegaven, a fish oil-based emulsion, with improved liver function among most patients. SUMMARY: PNALD remains the most severe complication of long-term parenteral nutrition with an unclear pathophysiology. However, the use of a fish oil-based emulsion appears efficacious and hepatoprotective.

Innovative parenteral and enteral nutrition therapy for intestinal failure.

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.

Three-month tolerability of orlistat in adolescents with obesity-related comorbid conditions.

OBJECTIVE: To study the safety, tolerability, and potential efficacy of orlistat in adolescents with obesity and its comorbid conditions. RESEARCH METHODS AND PROCEDURES: We studied 20 adolescents (age, 14.6 +/- 2.0 years; body mass index, 44.1 +/- 12.6 kg/m(2)). Subjects were evaluated before and after taking orlistat (120 mg three times daily) and a multivitamin for 3 months. Subjects were simultaneously enrolled in a 12-week program emphasizing diet, exercise, and strategies for behavior change. RESULTS: Participants who completed treatment (85%) reported taking 80% of prescribed medication. Adverse effects were generally mild, limited to gastrointestinal effects observed in adults, and decreased with time. Three subjects required additional vitamin D supplementation despite the prescription of a daily multivitamin containing vitamin D. Weight decreased significantly (-4.4 +/- 4.6 kg, p < 0.001; -3.8 +/- 4.1% of initial weight), as did body mass index (-1.9 +/- 2.5 kg/m(2); p < 0.0002). Total cholesterol (-21.3 +/- 24.7 mg/dL; p < 0.001), low-density lipoprotein-cholesterol (-17.3 +/- 15.8 mg/dL; p < 0.0001), fasting insulin (-13.7 +/- 19.0 microU/mL; p < 0.02), and fasting glucose (-15.4 +/- 7.4 mg/dL; p < 0.003) were also significantly lower after orlistat. Insulin sensitivity, assessed by a frequently sampled intravenous glucose-tolerance test, improved significantly (p < 0.02). DISCUSSION: We conclude that, in adolescents, short-term treatment with orlistat, in the context of a behavioral program, is well-tolerated and has a side-effect profile similar to that observed in adults, but its true benefit versus conventional therapy remains to be determined in placebo-controlled trials.