Russell J. Merritt

Evidence of Aluminum Loading in Infants Receiving Intravenous Therapy

To investigate the possibility that premature infants may be vulnerable to aluminum toxicity acquired through intravenous feeding, we prospectively studied plasma and urinary aluminum concentrations in 18 premature infants receiving intravenous therapy and in 8 term infants receiving no intravenous therapy. We also measured bone aluminum concentrations in autopsy specimens from 23 infants, including 6 who had received at least three weeks of intravenous therapy. Premature infants who received intravenous therapy had high plasma and urinary aluminum concentrations, as compared with normal controls: plasma aluminum, 36.78 +/- 45.30 vs. 5.17 +/- 3.1 micrograms per liter (mean +/- S.D., P less than 0.0001); urinary aluminum:creatinine ratio, 5.4 +/- 4.6 vs. 0.64 +/- 0.75 (P less than 0.01). The bone aluminum concentration was 10 times higher in infants who had received at least three weeks of intravenous therapy than in those who had received limited intravenous therapy: 20.16 +/- 13.4 vs. 1.98 +/- 1.44 mg per kilogram of dry weight (P less than 0.0001). Creatinine clearances corrected for weight did not reach expected adult values until 34 weeks of gestation. Many commonly used intravenous solutions are found to be highly contaminated with aluminum. We conclude that infants receiving intravenous therapy have aluminum loading, which is reflected in increased urinary excretion and elevated concentrations in plasma and bone. Such infants may be at high risk for aluminum intoxication secondary to increased parenteral exposure and poor renal clearance.

Cholestasis Associated with Total Parenteral Nutrition

It appears that neonates, especially those with very low birthweights, may be at especially high risk of developing cholestasis associated with total parenteral nutrition (TPN). Within 2 weeks of starting intravenous alimentation, it would appear highly desirable to be able to start at least small enteral feedings to interrupt the physiology of fasting. Such feedings may not have to be of much nutritional benefit to improve cholestasis. Calorie and amino acid intake should be limited to the requirements of the infant being treated. Whether protection of the TPN infusate from light is of benefit remains to be determined. Drug therapies for TPN-associated cholestasis of infancy have not been proven safe or effective. Additional investigations to further clarify the pathogenesis of this syndrome, and clinical studies of prophylaxis and therapy, are needed to enhance our ability to provide nutritionally effective and metabolically safe parenteral nutrition.

Nutrition in the Neonatal Intensive Care Unit: How Do We Reduce the Incidence of Extrauterine Growth Restriction?

Extrauterine growth restriction is a major clinical problem for prematurely born neonates, especially critically ill preterm neonates, and malnutrition in the neonatal intensive-care unit remains common. There are numerous perceived risks to initiation of adequate nutritional support. How many of these factors pose a real risk to health outcomes is less clear. Current nutritional support does not prevent extrauterine growth restriction and the consequences of malnutrition are both acute and delayed. Our clinical approach to providing nutritional support impacts neonatal morbidity and long-term neuro developmental outcomes. While more and better evidence is needed to help guide best practices, this gap should not prevent neonatologists from using the observations in this review to improve their current practice. There is evidence that changes in nutritional support can have a positive influence on growth. These include early administration of intravenous amino acids and lipids, minimal enteral nutrition, and supplemented formula and human milk. Simply recognizing the degree of growth failure by monitoring weight and focusing on the accruing deficit should encourage clinicians to increase nutritional support to enhance recovery growth. Continued research is needed to define the efficiency of early feeding, more rapid advancements in nutritional support, protein needs, the optimal composition of breast-milk supplements, the etiology of necrotizing enterocolitis, and perhaps most importantly, the health consequences of extrauterine growth restriction.

Effect of Nucleotides on Diarrhea and Immune Responses in Healthy Term Infants in Taiwan

ObjectivesThe aim of this study was to compare the effects of an infant formula fortified with nucleotides (NF) with those of a control formula (CF) on the incidence of diarrhea, respiratory tract infections (RTIs), and immune responses in healthy term infants. MethodsThis 12-month, double-blind study was conducted on 1- to 7-day-old infants randomized to receive NF or CF exclusively until 12 weeks of age, and fed the assigned formula with solid food until 12 months. NF was supplemented with 72 mg/L of nucleotides, based on the total potentially available nucleotide content of human milk. Subjects were evaluated within 1 week of birth, at 4 weeks, and every 4 weeks thereafter until 48 weeks of age. The primary outcome variable was the incidence of diarrhea. Secondary variables included RTIs, serum immunoglobulin concentrations, and response to hepatitis B vaccine. ResultsCompared with subjects fed CF (n = 170), those fed NF (n = 166) had a trend toward reduced risk of diarrhea from 8 to 48 weeks of age and a significantly lower risk of 25.4% (P = 0.05) between 8 and 28 weeks. NF subjects had significantly higher serum immunoglobulin A concentrations (P < 0.05) throughout the 48-week study. The NF group had an increased risk of upper RTIs, the same incidence of lower RTIs, and the same antibody response to hepatitis B vaccination as the CF group, based on one-sided tests. Growth was normal in both groups, and no adverse events were considered to be formula-related. ConclusionsHealthy term infants from 8 to 28 weeks of life are less likely to experience diarrhea and have higher serum immunoglobulin A concentrations with NF compared with formula without added nucleotides.

Whey protein hydrolysate formula for infants with gastrointestinal intolerance to cow milk and soy protein in infant formulas.

Twenty-one infants less than 6 months of age with gastrointestinal symptoms of cow milk and/or soy protein-based infant formula intolerance (diarrhea in 14, hematochezia in 16, emesis in 8, failure to thrive in 4, and colic in 10) were treated clinically with a whey protein hydrolysate formula. Six patients improved when placed directly on the formula, and 15 remained asymptomatic or improved when given the whey hydrolysate formula following initial treatment with a casein hydrolysate or elemental formula. Eighteen had supporting evidence of an allergic basis for their symptoms, including a family history of allergies in 6, a clinical challenge with the offending formula in 1, laboratory tests consistent with atopy in 11, and/or rectal biopsy with histologic allergic features in 7. The whey hydrolysate formula may be an acceptable alternative to soy or casein hydrolysate formulas in most infants with gastrointestinal symptoms of cow milk and/or formula intolerance.

Cholestatic Effect of Intraperitoneal Administration of Tryptophan to Suckling Rat Pups

Summary: The potential cholestatic effect of amino acids and metabolites of tryptophan were evaluated by use of seven daily intraperitoneal injections to suckling and weanling rat pups. Of the amino acids present in parenteral nutrition solutions, only tryptophan (given at a dose of 4 mM/kg) produced a significant (p < 0.01) elevation of serum cholylglycine (12.8 ± 1.0 μM/liter) as determined by radioimmunoassay, compared to 4.9 ± 0.4 μM/liter in salinetreated control animals. Total serum conjugates of cholic acid, as determined by radioimmunoassay, were similarly elevated, as was serum alanine aminotransferase. Tryptophan injection resulted in elevated cholylglycine concentrations only at doses of 3 mM/kg/day or higher. Animals more than 2 weeks old did not demonstrate elevation of serum cholylglycine. Injection of light-exposed tryptophan in suckling animals caused a greater elevation of cholylglycine (39.0 ± 8.6 μM/liter) than freshly prepared tryptophan solutions (p < 0.005). Tryptophan and its spontaneous degradation products could contribute to the cholestatic liver changes observed during parenteral nutrition therapy.

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.

Safety evaluation of sources of docosahexaenoic acid and arachidonic acid for use in infant formulas in newborn piglets

Human milk provides small quantities of preformed docosahexaenoic acid (DHA) and arachidonic acid (ARA), usually less than 1% of total fatty acids. Vegetable oil blends commonly used in infant formulas have, until recently, provided the essential fatty acid precursors for these long-chain polyunsaturated fatty acids (LCPUFA), but no preformed DHA and ARA. This study evaluated the safety of ingredient sources of DHA and ARA for use in infant formulas in a neonatal piglet model. Newborn piglets were allowed to suckle for 3 days and then divided into 4 feeding groups of 6 males and 6 females. Piglets were bottle-fed at frequent feeding intervals until 19 days of age. The composition of the piglet formulas was modeled after standard milk-based formulas for human infants while meeting nutritional requirements for piglets. Formulas were a control formula (no added DHA or ARA), a DHA formula providing 55 mg DHA/100 Cal, an ARA formula providing 96 mg/100 Cal ARA, and a DHA+ARA formula providing 34 mg DHA and 62 mg ARA/100 Cal. All formulas were equal in fat content and provided approximately 1000 Cal/l. The ARA-rich oil was from a fermentation product of Mortierella alpina (40 wt.% fatty acids as ARA) and DHA was from high DHA tuna oil (25 wt.% fatty acids as DHA). There were no test article related effects of DHA and/or ARA indicative of an adverse health consequence to the animals seen in the clinical signs, body weights, food consumption, clinical chemistry, hematology, organ weights or gross or histopathology. The findings in this neonatal animal study support the safety of these ingredient oil sources of DHA and ARA for use in infant formulas.

Phenobarbital Does Not Prevent Total Parenteral Nutrition-Associated Cholestasis in Noninfected Neonates

Cholestasis associated with total parenteral nutrition (TPN) is a serious complication of this therapy for which there is no known treatment other than beginning enteral feeds. Phenobarbital is commonly used in other cholestatic disease states, but its benefit in this syndrome has not been demonstrated. We conducted a retrospective review of phenobarbital use in neonates receiving concurrent TPN. Thirty-one noninfected neonates were studied. They were without evidence of intrinsic liver disease at the institution of exclusive TPN therapy. For the purposes of this study, TPN-associated cholestasis was defined as a serum bilirubin in excess of 3 mg/dl at postnatal age of 3 weeks or more. Fourteen of the study infants received phenobarbital therapy for neurologic indications. Sixty percent of the phenobarbital-treated infants developed TPN-associated cholestasis, as compared to 33% of the untreated patients. Phenobarbital therapy was not effective in preventing TPN-associated cholestasis.

Use of Hickman Right Atrial Catheter in Pediatric Oncology Patients

Eighteen pediatric oncology inpatients had 21 Hickman right atrial catheters placed for total venous access; 16 patients received parenteral nutrition. Mean duration of catheterization was 43 +/- 29 (SD) days. Four catheters had to be removed for infection or clotting. The catheter-related sepsis rate was 10%. Serious catheter-related complications were no more frequent in this population than in patients receiving only parenteral nutrition via Broviac or pediatric Broviac catheters.