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Purpose: Prefilled drug syringe use may reduce the cost of routine antibiotic drug delivery. Storage of prefilled syringes frozen (-20°C) or refrigerated (4°C-5°C), can optimize the use of robotic syringe filling systems if acceptable stability data is gathered per USP 797 standards. Methods: Four intravenous (IV) drug formulations were prepared from bulk standard solutions and filled into 10 mL syringes using an Intellifill© IV Robot. Formulations were Piperacillin (2.0 g) and Tazobactam (0.25 g) as 2.25 g in 10 mL; Piperacillin (3.0 g) and Tazobactam (0.375 g) as 3.375 g in 10 mL; Cefuroxime as 1.5 g in 11 mL; and Vancomycin as 1.0 g in 10 mL. Concentrations were assayed at "zero time," and after 21, 45, and 60 days frozen. Syringes were warmed to room temperature (RT) by gently rolling in hands. Three syringes of each formulation were assayed by stability-indicating HPLC per USP procedures. Assay results are the average of 5 injections of samples from each syringe upon return to RT and repeated for 3 separate syringes maintained at RT for 24 hours. Results: All formulations were stable out to 60 days frozen. Both of the piperacillin/tazobactam formulations were also stable when kept at refrigerated temperature for 9 days. Conclusion: Piperacillin/Tazobactam formulations can be stored frozen (-20°C) for up to 60 days with no appreciable loss. Cefuroxime and Vancomycin formulations can be stored frozen for up to 60 days. Both Piperacillin/Tazobactam formulations can be refrigerated for up to 9 days. Implementation of larger batch compounding coupled with frozen syringe storage and delivery could result in enhanced uniformity of composition and significant manpower savings., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Introduction: Citrulline is synthesized primarily in enterocytes. Retrospective work revealed higher plasma concentrations in patients without gastrointestinal (GI) disease than in those with GI disease, regardless of bowel resection, leading us to speculate whether it could be used as a marker of gut function prospectively. Our purpose was to analyze plasma citrulline in these patients, comparing a period of exclusive parenteral nutrition (PN) vs both PN and enteral nutrition (PN/EN)., Methods: Premature neonates were included in this study. Plasma samples were collected during 2 periods, PN and PN/EN. They were classified into groups: patients without GI disease (Group 1), patients with GI disease without resection (Group 2), and patients with GI disease and resection (Group 3). Plasma was analyzed by high-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Data were described as median with ranges., Results: Fifty patients were recruited for this study, from which 164 samples were obtained and analyzed by LC-MS. Median plasma citrulline concentrations were 12.3 (5.6-39.4) µmol/L, 14.9 (6.8-39.8) µmol/L, and 10.8 (2.0-23.6) µmol/L for Groups 1, 2, and 3, respectively. After Bonferroni correction, only Group 3 had a significantly different median from the others. No differences were observed within periods of nutrition (PN vs PN/EN). Postconceptual age (PCA), among others, was assessed to determine differences for which the former demonstrated significance., Conclusion: Premature neonates with bowel resection had lower plasma citrulline concentrations, confirming its role as gut mass marker, though without differences during transitional feeding. PCA may affect expression of this protein., (© 2019 American Society for Parenteral and Enteral Nutrition.)

As seen over the past 20 years, calprotectin has evolved as a novel, non-invasive biomarker of gastrointestinal (GI) inflammation. We present this review of calprotectin in pediatrics. This article will focus on studies using calprotectin concentrations from different body fluids to monitor inflammation in different disease states and conditions. The ultimate goal of our group is to lay down a foundation as we consider using calprotectin prospectively as a marker of intestinal inflammation that could lead to further testing and possibly a marker of preparedness for feeding. We surveyed all published studies in English of calprotectin in neonates, infants, children, and adolescents through February 2014. We will discuss calprotectin's basic properties and analysis such as characteristics, identification, presence in body fluids, and maturational development. In addition, calprotectin's use in inflammatory diseases exploring both GI and non-GI conditions will be evaluated and compared with other serum markers presently available. Finally, a summary of our findings and discussion of future work that could be undertaken in order to render calprotectin as a more useful monitoring tool to the medical research community will complete the review.

Background: Omega-3 long-chain polyunsaturated fatty acids (ω3PUFA) have been shown to be antiinflammatory in the attenuation of hepatocellular injury. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor transcription factor that inhibits the activation of nuclear factor κB, thereby repressing inflammation, and ωPUFA are PPARα ligands. The purpose of this study was to determine if ω3PUFA attenuate bile acid-induced apoptosis via PPARα., Methods: Human hepatocellular carcinoma (HepG2) cells were treated with chenodeoxycholic acid (CDCA) ± ω3PUFA. Activation of PPARα was evaluated, and expression of PPARα, farnesoid X receptor, liver X receptor alpha (LXRα), and retinoid X receptor mRNA was evaluated by reverse-transcriptase PCR., Results: PPARα activation was increased in HepG2 cells treated with ω3PUFA, and decreased in the presence of CDCA when compared with untreated cells. PPARα mRNA was reduced by 67% with CDCA and restored to the level of control with ω3PUFA. LXRα mRNA increased twofold with CDCA treatment and was significantly reduced by ω3PUFA., Conclusion: Expression of PPARα, as well as LXRα mRNA levels, was reduced with CDCA treatment and restored with the addition of ω3PUFA. These results suggest that PPARα and LXRα may be mediators by which ω3PUFA attenuate bile acid-induced hepatocellular injury.

Background: Clinical studies have demonstrated improvement of parenteral nutrition (PN)-associated liver disease (PNALD) with ω3 polyunsaturated fatty acid (ω3PUFA) supplementation containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Experiments were designed to test the following hypotheses: (1) therapeutic effects of ω3PUFA are due to attenuation of cellular apoptosis induced by hydrophobic bile acid exposure, which occurs in cholestasis, and (2) attenuation of apoptosis by EPA and DHA is additive or synergistic., Methods: Cultured HepG2 cells were treated with 50-200 µM chenodeoxycholic acid (CDCA) in the presence and absence of EPA, DHA, or EPA + DHA. Apoptosis was evaluated using cell staining with fluorescence microscopy and the Apo-ONE Homogeneous Caspase-3/7 assay. Specific apoptotic mediators were evaluated with quantitative RT-PCR., Results: Treatment with EPA alone and DHA alone resulted in 22% and 9% attenuation of caspase-3/7 activity, respectively. Caspase-3/7 activity was attenuated by 52% when cells were treated with a combination of EPA and DHA (P = .0034). Treatment with EPA alone, DHA alone, and the combination of EPA and DHA all resulted in equal attenuation of apoptotic mediator gene expression., Conclusions: The combination of EPA and DHA resulted in a synergistic attenuation of bile acid-induced hepatocellular apoptosis, as assessed by caspase-3/7 activity, compared to EPA and DHA separately. The combination of EPA and DHA did not result in a synergistic attenuation of the upregulation of Fas or TRAIL-R2. These data suggest that EPA and DHA may be working via multiple intracellular pathways to attenuate bile acid-induced apoptosis.

Background: Citrulline is a nonessential amino acid produced solely in the enterocyte. Plasma citrulline concentration has been proposed as a noninvasive biomarker for bowel length, function, and dependency on parenteral nutrition (PN). The purpose of this study was to determine if citrulline concentrations differed between pediatric patients with and without small bowel loss requiring specialized nutrition support., Methods: This was a retrospective categorical analysis of citrulline concentrations from previously published studies. Patients were included if they were receiving PN, more than 30 days of age, and if they had at least 2 plasma citrulline concentrations. Patients with renal insufficiency and who received outpatient PN treatment were excluded. Patients were categorized as either having or not having small bowel loss., Results: Thirty-six patients were included for analysis (18 per category). The median citrulline concentration was significantly lower in the group with bowel loss, 8.4 µmol/L vs 10.5 µmol/L (P < .0005), and undetectable citrulline concentrations occurred more often in the bowel loss group, 40% vs 8% (P < .0005). In 13 patients who received enteral nutrition during the study periods, plasma citrulline concentrations increased only in patients without bowel loss., Conclusions: These data confirm previous studies and identify decreased citrulline concentrations in pediatric patients with bowel dysfunction in the absence of bowel loss. These data also represent the first serial citrulline concentrations over a 21-day period. The increase in citrulline concentrations only in fed patients without bowel loss suggests that citrulline concentrations could provide a biomarker for bowel function and adaptation.

Study Objective: To evaluate the use of enteral fish oil for the treatment of parenteral nutrition-associated liver disease (PNALD)., Design: Retrospective case series., Setting: Pediatric academic hospital and outpatient clinic., Patients: Six parenteral nutrition-dependent infants with short-bowel syndrome and PNALD., Measurements and Main Results: The six infants received supplementation with enteral fish oil, and treatment was evaluated over a 12-week period. The PNALD, as reflected by elevated total bilirubin levels, completely reversed in four of the six infants within a mean ± SD of 5 ± 2.6 weeks (range 2-8 wks) after initiation of the enteral fish oil supplementation. In addition, improvement in enteral feedings occurred after starting enteral fish oil therapy., Conclusion: Enteral fish oil may be an effective adjunctive treatment option for infants with PNALD, particularly for those infants with PNALD who are tolerating some amount of enteral nutrition as the result of an adequate amount of small bowel.

Parenteral nutrition-associated liver disease (PNALD) is a complex disease that is diagnosed by clinical presentation, biochemical markers of liver injury, concurrent use of parenteral nutrition (PN), and negative workup for other causes of liver disease. For the past 30 years, clinicians have had few effective treatments for PNALD and when disease progressed to liver cirrhosis it was historically associated with poor outcomes. Within the past 5 years there has been some encouraging evidence for the potential benefits of fish oils, rich in omega-3 long-chain polyunsaturated fatty acids (ω3PUFA), in reversing liver injury associated with PN. This article reviews the current literature relating to ω3PUFA and PNALD.

Purpose: Microbial contamination associated with different methods of neonatal intravenous fat emulsion (IVFE) preparation and delivery was evaluated., Methods: Sterility testing was performed on IVFE dispensed via three different methods: (1) in the original container (n = 60), (2) repackaged into a syringe (n = 90), and (3) drawdown of the original container (n = 60). At the end of each infusion (24 hours for methods 1 and 3, 12 hours for method 2), a sample of the IVFE was withdrawn from the container using a sterile syringe in an International Organization for Standardization class 5 hood and sent to the hospital microbiology laboratory, where the samples were introduced into blood culture bottles and incubated for five days. Each sample was then subcultured on a blood agar plate with olive oil and left for an additional two days in a carbon dioxide incubator to assess for Malassezia furfur., Results: None of the samples from the original containers showed bacterial or fungal growth. Three of the samples from syringes had bacterial growth (two samples contained coagulase-negative staphylococcus and one contained both Klebsiella oxytoca and Citrobacter freundii), yielding a contamination rate of 3.3%. The number of contaminated samples did not significantly differ among the three preparation methods (p = 0.13)., Conclusion: Repackaging IVFE into sterile syringes resulted in bacterial contamination and should be avoided in clinical practice. IVFE samples obtained using the drawdown procedure under sterile conditions for infusion over 24 hours revealed no microbial contamination.

Background: Plasma amino acid (PAA) levels can be largely normalized during parenteral nutrition (PN) in infants and children using a pediatric-specific amino acid (AA) formulation. However, these previous results were based on individual clinical studies of small populations of neonates and infants., Objective: We have now examined AA levels in 108 children (0-7 years of age) receiving a pediatric-specific AA formulation in PN using a single analytical methodology., Methods: Infants and children were enrolled in specific protocols and parents/caregivers gave informed consent. Patients were stable and receiving age-appropriate intakes of AA and non-protein calories. Samples were obtained between 8 and10 am, processed immediately, deproteinized, and AA concentrations (μmol/L) were determined on a Beckman 6300 analyzer. Means and SD were calculated for sub-populations stratified by age: 0-1 month (48 patients, n=139), 1-6 months (36 patients, n=124), 7-12 months (11 patients, n=41), and 1-7 years (13 patients, n=51). Z scores were calculated for each amino acid [(observed mean - normal control mean)/normal control SD]., Results: When compared to the neonatal reference range, nonessential AA had Z scores that ranged from -1.84 (asparagine) to +1.48 (threonine). Only plasma free cystine, free tyrosine, and phenylalanine had Z scores outside the -2.0 to +2.0 range (95% confidence limits). Plasma free cystine values were low in all groups except neonates. Free tyrosine levels were low in all groups despite the presence of N-acetyl-L-tyrosine in the pediatric AA formulation. Phenylalanine levels were elevated only in neonates. When children 1 to 7 years old were compared with an age-matched reference range, plasma free cystine values were low (Z score -2.47), as were plasma glutamine values (-3.11), but elevations were found in the dicarboxylic amino acids aspartic acid (+2.5) and glutamic acid (+4.27). Regardless of reference range used for comparison, all essential amino acids, except phenylalanine in neonates, were within range (-2 to +2 of the 95% confidence limits)., Conclusions: While most AAs were within the normal range, formulation modifications are needed to normalize free cystine in infants and young children, free tyrosine in all children, and phenylalanine in neonates. The decrease in glutamine concentrations in older children has been noted by our group before, and may imply limited ability to convert glutamic acid to glutamine, or increased consumption of glutamine. In either case, increased concentrations of glutamine in older children, especially those receiving home parenteral nutrition, should be considered.

Background & Aims: Carnitine may be considered conditionally essential in the neonatal population. The purpose of this study was to evaluate the effects of long-term carnitine supplementation on total carnitine status and morbidity in premature neonates., Methods: In this prospective, randomized, placebo-controlled, double-blinded study, premature neonates received carnitine supplementation (20mg/kg/day) or placebo. Plasma (nmol/ml) and red blood cell (RBC) (nmol/mg hemoglobin) total carnitine concentrations, 24-h nitrogen excretion, intake and weight, and respiratory, gastroesophageal, and infectious morbidity were assessed., Results: Twenty-nine neonates (13 placebo, 16 carnitine; 27+/-2 weeks gestation; 976+/-259g birthweight) were studied for up to 8 weeks. Plasma total carnitine concentrations exceeded the reference range in the carnitine group (weeks 1-8); however, concentrations did not reach reference range until week 4 in the placebo group. RBC total carnitine concentrations increased, but remained below reference range in both the carnitine (weeks 1-6) and placebo (weeks 1-8) groups. Carnitine group neonates regained their birthweight more rapidly than placebo group neonates (day of life 11.8+/-6 vs. 16.9+/-6.3, P=0.034). In addition, percent periodic breathing calculated from cardiopulmonary trend monitor data (weeks 1-8) was lower in the carnitine group (0.4+/-0.9 vs. 1.4+/-1.9, P=0.014). There was no difference with respect to other markers of respiratory, gastroesophageal and infectious morbidity or nitrogen balance., Conclusions: Carnitine supplementation at 20mg/kg/day results in increased plasma and RBC total carnitine concentrations, has a positive effect on catch-up growth, and may improve periodic breathing in premature neonates.

Background: Carnitine is an important nutrient in the infant diet. We compared total plasma carnitine concentrations in premature neonates supplemented with carnitine via parenteral and enteral nutrition., Methods: This is a post hoc analysis of plasma total carnitine concentrations and carnitine intake in neonates randomized in a previous study to receive 20 mg/kg/d carnitine supplementation over 8 weeks. Neonates received l-carnitine initially via parenteral nutrition (PN). When neonates were fed enterally, oral supplementation of l-carnitine was given in divided doses with each feeding., Results: Sixteen neonates (27 +/- 2 weeks gestation; 2.9 +/- 1.0 days postnatal age at enrollment; 965.6 +/- 279.1 g birth weight) are included. Concentrations were below reference range (31.1-60.5 nmol/mL) at baseline and exceeded reference range from week 1 through the last study period. Concentrations were not different from week 1 (108 +/- 49) through weeks 4 (87 +/- 34) and 8 (83 +/- 31). Carnitine intakes and concentrations were compared in neonates receiving 100% parenteral carnitine at week 1 (n = 6) and 100% enteral carnitine at week 8 (n = 8). Concentrations at week 1 (100.1 +/- 27.9) were not different (p = .19) from week 8 (78.6 +/- 29.3); an estimate of relative bioavailability was 78.6%. Bioavailability with paired analysis of neonates (n = 5) receiving 100% parenteral carnitine at week 1 and 100% enteral carnitine at week 8 was 83.7% +/- 41.2% (30.1%-140.6%)., Conclusions: Parenteral and enteral supplementation of 20 mg/kg/d carnitine results in plasma total carnitine concentrations that exceed the reference range. Concentrations are not different between parenteral to enteral supplementation, suggesting that enteral carnitine is well absorbed when given daily in divided doses with enteral feedings.

Objective: We compared markers of protein metabolism between children who had a controlled injury and an acute traumatic event. Significant protein catabolism occurs after acute severe injury. During surgery the injury is controlled and the degree of subsequent catabolism may be blunted., Methods: This was a prospective, unblinded observational study in 10 children 2 to 12 years old with a closed head injury (CHI) and an admission Physiologic Stability Index of ≥ 10 and in 10 children who underwent elective cardiothoracic surgery (CTS). Nutrient intake, nitrogen balance, serum albumin and prealbumin, urinary 3-methylhistidine excretion, and 3-methylhistidine to creatinine ratios were evaluated on days 1, 2, 3, 4, and 10 after injury., Results: Nutrient intake was similar in both groups on study days 1-4 and did not meet estimated needs. By day 10, 7 patients in the CTS group and 2 patients in the CHI group had been discharged home. The 3 CTS patients were still in the ICU while the 8 hospitalized CHI patients had been transferred to the floor. Compared to the CTS group, nitrogen balance in the CHI group was lower on day 1. On day 10, nitrogen balance and prealbumin were greater in the CHI group than in the CTS group, consistent with recovery and increased nutrient intake., Conclusions: Markers of protein metabolism follow similar patterns after CTS or CHI in children. However, markers of protein metabolism indicate more severe catabolism soon after injury in CHI.

Serum, urine, and parenteral nutrition (PN) chromium and zinc concentrations in pediatric patients receiving long-term PN were studied. Serum, urine, and PN chromium and zinc concentrations were measured at baseline and four to six months later in four infants (less than 1 year old) and seven children (1-12 years old) receiving long-term PN. In the children, serum, urine, and PN solution zinc concentrations were measured monthly after the amino acid product was changed from a standard to a pediatric product with monthly dosages of 0, 20, 30, and 40 mg of cysteine hydrochloride per gram of amino acids. The mean +/- S.D. baseline serum chromium concentration was 4.9+/-1.9 microg/L (normal value, <0.3 microg/L); the urine chromium concentration ranged from 3.4 to 32.2 microg/L. The mean +/- S.D. prescribed chromium dosage was 0.18+/-0.05 microg/kg/day, and the dosage delivered in PN solutions was 0.41+/-0.23 microg/ kg/day. At baseline, the mean +/- S.D. serum zinc concentration was 1383+/-472 microg/L (normal range, 430 to 940 microg/L), and the prescribed and delivered zinc dosages were 177+/-10 and 238+/-145 microg/kg/ day, respectively. With 20, 30, and 40 mg of cysteine per gram of amino acids, the mean +/- S.D. serum zinc concentration was 1728+/-782, 1664+/-349, and 1685+/-268 microg/L, respectively, and the actual zinc dosages delivered were 209+/-10, 270+/-148, and 322+/-194 microg/kg/day, respectively. Serum and urine chromium concentrations were abnormally high in infants and children receiving PN solutions supplemented with normal doses of these trace elements; an escalating dosage of cysteine in the children tended to increase serum and urine zinc concentrations.

We evaluated plasma sulfur amino acid concentrations in children with short gut syndrome receiving home parenteral nutrition (n = 6). Cysteine HCl addition to solutions formulated with a pediatric amino acid product will increase plasma taurine concentrations to within the normal reference range.

Chromium and zinc contamination of components of parenteral nutrient (PN) solutions used in infants and children was studied. Solutions of amino acids, L-cysteine hydrochloride, dextrose, electrolytes, minerals, vitamins, multiple trace elements, and individual trace elements were obtained. A variety of manufacturers, lots, and expiration dates were represented when possible. The solutions were analyzed for chromium and zinc by flame atomic absorption spectrophotometry. In all amino acid products, chromium concentration was below the limit of detection and zinc concentration ranged from 0.06 to 4.97 mg/L. In the L-cysteine hydrochloride products, chromium was measurable in only two lots (0.11 and 0.23 mg/L); zinc was measurable in all lots (32-86 mg/L). Sodium and potassium salts of chloride and acetate had chromium concentrations of 0.02-0.23 mg/L and zinc concentrations of 0.35-0.56 mg/L. Phosphate salts contained chromium 0.39-0.44 mg/L and zinc 0.91-2.33 mg/L. In calcium gluconate, zinc concentration was 0.28-2.38 mg/L. In four lots of multiple trace elements, chromium was 92-104% and zinc was 100-113.5% of the labeled amount. A PN solution for a < 10-kg infant compounded from the components assayed would provide up to an additional 0.7 microgram of chromium per kilogram and 200 micrograms of zinc per kilogram. Zinc and chromium contaminants were detected in many of the products that are common components of PN solutions for infants and children; the contamination may be sufficient to result in the administration of zinc and chromium in amounts exceeding current recommendations.

The importance of taurine in the diet of pre-term and term infants has not always been clearly understood and is a topic of interest to students of infant nutrition. Recent evidence indicates that it should be considered one of the "conditionally essential" amino acids in infant nutrition. Plasma values for taurine will fall if infants are fed a taurine-free formula or do not have taurine provided in the TPN solution. Urine taurine values also fall, which is indicative of an attempt by the kidney to conserve taurine. The very-low-birth-weight infant, for a variety of reasons involving the maturation of tubular transport function, cannot maximally conserve taurine by enhancing renal reabsorption and, hence, is potentially at greater risk for taurine depletion than larger pre-term or term infants, and certainly more than older children who have taurine in their diet. Taurine has an important role in fat absorption in pre-term and possibly term infants and in children with cystic fibrosis. Because taurine-conjugated bile acids are better emulsifiers of fat than glycine-conjugated bile acids, the dietary (or TPN) intake has a direct influence on absorption of lipids. Taurine supplementation of formulas or TPN solutions could potentially serve to minimize the brain phospholipid fatty acid composition differences between formula-fed and human milk-fed infants. Taurine appears to have a role in infants, children, and even adults receiving most (> 75%) of their calories from TPN solutions in the prevention of granulation of the retina and electroencephalographic changes. Taurine has also been reported to improve maturation of auditory-evoked responses in pre-term infants, although this point is not fully established. Clearly, taurine is an important osmolyte in the brain and the renal medulla. At these locations, it is a primary factor in the cell volume regulatory process, in which brain or renal cells swell or shrink in response to osmolar changes, but return to their previous volume according to the uptake or release of taurine. While there is a dearth of clinical studies in man concerning this volume regulatory response, studies in cats, rats, and dog kidney cells indicate the protective role of taurine in hyperosmolar stress. The infant depleted of taurine may not be able to respond to hyper- or hyponatremic stress without massive changes in neuronal volume, which has obvious clinical significance. The fact that the brain content of taurine is very high at birth and falls with maturation may be a protective feature, or compensation for renal immaturity Defining an amino acid as "conditionally essential" requires that deficiency result in a clinical consequence or consequences which can be reversed by supplementation. In pre-term and term infants, taurine insufficiency results in impaired fat absorption, bile acid secretion, retinal function, and hepatic function, all of which can be reversed by taurine supplementation. Therefore, this small beta-amino acid, taurine, is indeed conditionally essential.

In the infant on parenteral nutrition, cysteine supplementation has been suggested due to low levels of hepatic cystathionase activity limiting synthesis from methionine. We have examined the plasma concentrations of sulfur amino acids in four groups of post-surgical infants requiring parenteral nutrition receiving (A) a low methionine + cysteine + taurine formula, (B) a high methionine formula (non-steady state), (C) a high methionine formula (steady state), and (D) a high methionine + cysteine formula. Plasma methionine concentrations were above the normal reference range (2.2-4.9 micromol/dL) of normal breast-fed infants in Groups B (15.9 +/- 10.7 micromol/dL) and D (5.7 +/- 1.9 micromol/dL) and at the upper limit for Group C (4.9 +/- 1.7 micromol/dL). Total cysteine/cystine concentrations (normal reference range, 10.2-20.4 micromol/dL) were highest in Groups A (18.9 +/- 3.5 micromol/dL) and D (16.8 +/- 5.3 micromol/dL) that received cysteine HCI supplementation, and lowest in Group B (8.6 +/- 3.7 micromol/dL) that received no cysteine in non-steady state. All plasma free cystine concentrations were below the normal reference range (3.6-6.8 micromol/dL). Plasma taurine concentrations were not significantly different among the four groups and all were within the normal reference range (0.6-16.2 micromol/dL). The strikingly elevated methionine and low total cysteine/cystine values in Group B suggested the existence of a feedback loop of methionine conversion below the level of homocysteine. Equilibrium of methionine and cysteine/cystine plasma concentrations did occur, in time. Parenteral cysteine administration resulted in a greater proportion of plasma free cysteine concentration, but not cystine. The proportion of free to bound cysteine/cystine, as well as the proportion of free cystine to cysteine, was not normal during parenteral nutrition with or without cysteine HCI supplementation. Little benefit in plasma concentrations was derived from cysteine HCI supplementation to a high methionine formulation.

Nitrogen excretion is a useful measurement for determining efficiency of protein utilization. Knowledge of nitrogen losses is especially important in the treatment of stressed, postsurgical, or catabolic patients, in whom optimizing the amount of nitrogen intake in the diet may spare visceral and somatic proteins and encourage anabolism. Many methods have been used to estimate total urinary nitrogen (TUN) in different patient populations. Urinary urea nitrogen (UUN) values are routinely adjusted and used by investigators who are not able to measure TUN directly by either Kjeldahl or pyrochemoluminescent methods. The rationale for the use of adjusted UUN concentrations to predict TUN is based on adult experiences. No similar experience in pediatrics has been published. We have compared TUN with adjusted UUN in a study of 250 urine samples from pediatric patients (n = 34) and normal pediatric volunteers (n = 109). Our findings suggest that adjusted UUN (determined by previously established formulas) may be of limited use in estimating TUN in neonates, infants, and critically ill pediatric patients; however, adjusted UUN may be useful in approximating TUN in healthy school-aged children. Good correlations were found between UUN and TUN for critically ill children and postsurgical neonates and infants, suggesting that these newly described regression equations (once validated) may be useful in predicting TUN from a measured UUN.

Objective: To assess the effect of parenteral amino acid solutions on plasma amino acid concentrations in patients with acute nonlymphocytic leukemia (ANLL) receiving parenteral nutrition (PN)., Design: Ten patients were studied at diagnosis, on the morning PN was started, and three times during PN therapy coinciding with the sequential administration of three different amino acid solutions (Aminosyn, FreAmine HBC, and TrophAmine). The order of amino acid solution administration in each patient was by a randomized, block design., Results: The patients were undergoing identical intensive induction therapy. There was no significant difference in the number of days they received PN or the amount of protein or calories received during the three PN study periods. At diagnosis, phenylalanine and glutamic acid concentrations were elevated compared with previously published normal values and remained elevated at all observation times. During PN, asparagine, aspartic acid, and tyrosine concentrations were significantly lower with all three amino acid solutions compared with their concentrations at diagnosis. Glycine and threonine concentrations were also significantly lower with FreAmine HBC and TrophAmine administration and cysteine concentrations were significantly lower with FreAmine HBC administration than at the time of diagnosis. Aminosyn was associated with plasma amino acid concentrations most similar to those measured at diagnosis., Conclusions: These results indicate that most amino acid concentrations fall within the normal range at diagnosis in the ANLL patients studied. Plasma concentrations for certain amino acids can be influenced by the amino acid solution used in PN. Further understanding of the derangements in amino acid metabolism and the influence of parenterally administered amino acid solutions on plasma amino acid concentrations may lead to improvements in the nutritional support of cancer patients.

Minimal information is available defining urinary nitrogen constituents in preterm neonates receiving parenteral nutrition (PN). The study objective was to evaluate 24-hour urine collections for total urinary nitrogen (TUN), urinary urea nitrogen (UUN), and the nitrogen content in creatinine, ammonia, free amino acids, protein, hippuric acid, and uric acid at baseline (days 1 to 2 of PN and days 1 to 3 after surgery) and 7 days later in eight preterm, postsurgical neonates. Calculation of undetermined nitrogen was also completed. Comparisons with historic, normal data were made for each urinary nitrogen constituent. At baseline, PN provided 59 +/- 10 nonprotein kcal/kg.day-1 and 430 +/- 54 mg/kg.day-1. At day 7, PN provided 106 +/- 23 nonprotein kcal/kg.day-1 and 432 +/- 30 mg/kg.day-1. TUN, UUN, and protein nitrogen decreased significantly from baseline at day 7 (p < .05). The percentages of TUN as amino acids, creatinine, and uric acid nitrogen were calculated. Percent amino acid nitrogen (6.0 +/- 2.3% vs 8.4 +/- 1.5%, p < .05), percent creatinine nitrogen (1.6 +/- 0.5% vs 2.9 +/- 0.8%, p < .001) and percent uric acid nitrogen (1.7 +/- 0.9% vs 3.6 +/- 2.1%, p < .05) increased significantly at day 7. The observed urinary free amino acid nitrogen fraction represented a higher percentage of TUN both at baseline and at day 7 when compared with term neonatal reference data, whereas creatinine nitrogen, uric acid nitrogen, and protein nitrogen represented a lower percentage of TUN. However, amino acid and creatinine nitrogen as a percentage of TUN were similar to levels in milk formula-fed preterm infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Critically ill patients have unique nutritional substrate requirements. Although important advances have been made in understanding these requirements in the face of pathophysiologic and biochemical alterations induced by stress or trauma, nutrition-associated toxicities still occur. The importance of these toxicities to the critically ill patients cannot be over-stated. Many of these toxicities can be avoided by conservative use of selected nutrition substrates in specific subsets of the critically ill population. Practitioners must continue to anticipate and recognize parenteral nutrition-associated toxicities, however, as well as delineate any toxicity from the progression or exacerbation of disease.

To determine whether intravenous carnitine can improve nutritional indices, neonates requiring parenteral nutrition were randomized into carnitine treatment (n = 23) and control (n = 20) groups. Observed plasma lipid indices, carnitine and nitrogen balances, and plasma carnitine concentrations were not different in the prestudy period. Under standardized, steady-state conditions, 0.5 g/kg Intralipid was administered intravenously over 2 hr prior to carnitine administration, after infants received 7 days of 50 mumol/kg/day, and after a second 7 days of 100 mumol/kg/day of continuous intravenous L-carnitine as part of parenteral nutrition. Triglyceride (TGY), free fatty acid (FFA), acetoacetate (AA), beta-hydroxybutyrate (BOB), and plasma carnitine concentrations were measured prior to and at 2, 4, and 6 hr after the initiation of the lipid bolus. Twenty-four-hour urine collections for nitrogen and carnitine balance were obtained on days 7 and 14. Neonates receiving carnitine had significantly greater concentrations of plasma carnitine on days 7 and 14 (p less than 0.001). Greater nitrogen (p less than 0.05) and carnitine (p less than 0.001) balances and weight gain (week 2, p less than 0.05) were found in the carnitine-supplemented group when compared with controls. On day 14, (BOB + AA)/FFA ratios were significantly higher (p less than 0.05), and peak TGY concentrations and 6-hr FFA concentrations were significantly lower (p less than 0.05) in the treatment group. Carnitine supplementation was associated with modest increases in growth and nitrogen accretion possibly by enhancing the neonate's ability to utilize exogenous fat for energy.

Aspirin and acetaminophen are the most widely used antipyretics in pediatrics. Most clinicians believe the drugs to be equally effective, though clinical opinion often suggests that aspirin is more effective at higher temperatures. Fifty-nine outpatients (age range, 2-8 years), presenting with rectal temperatures of 38.8 to 40.5 degrees C, were enrolled in this double-blind trial. The children were stratified by weight and initial temperature. One dose of chewable aspirin or acetaminophen (10-15 mg/kg based on current recommendations for weight) was administered, and rectal temperatures were monitored for three hours. Of the 59 patients enrolled, 46 successfully completed the protocol. Both drugs significantly reduced temperatures in the groups studied. Age did not influence the response of the children to the antipyretic effects of either drug. Aspirin and acetaminophen appeared equally effective when initial temperatures were between 38.8 and 39.9 degrees C. However, when the initial temperature was between 40.0 and 40.5 degrees C, the duration of effect of acetaminophen was shorter than that for aspirin. This suggests that therapeutic differences in the antipyretic activities of aspirin and acetaminophen may exist at higher temperatures.

A mixture of amino acids designed to maintain normal plasma amino acid concentrations of infants and children requiring parenteral nutrition was evaluated in 40 infants and children receiving only parenteral nutrients (2.39 +/- 0.26 g/kg/d of amino acids and 110.3 +/- 10.4 kcal/kg/d) for five to 21 days. The children ranged in weight from 2.0 to 12.6 kg (median weight, 3.83 kg; fifth to 95th percentile, 2.06 to 11.1 kg) and in age from 1 week to 43.6 months (median age, 2.7 months; fifth to 95th percentile, 0.2 to 25.3 months). Mean weight gain was 11.0 +/- 5.0 g/kg/d; mean nitrogen balance was 242 +/- 70 mg/kg/d. Plasma concentrations of all amino acids except tyrosine were within the normal range (ie, within the 95% confidence limits of the two-hour postprandial plasma concentrations observed in 30-day-old, healthy, normally growing, breast-fed, term infants) throughout the period of study. Mean prestudy and poststudy serum total protein, albumin, and transthyretin (prealbumin) concentrations were not significantly different. However, plasma transthyretin concentration increased in all children with low prestudy concentrations. Mean poststudy serum total bilirubin concentration of the total population was not different from the mean prestudy concentration. This was true also for the 31 children who received the parenteral amino acid mixture for more than ten days. In contrast to the expected 30% to 50% incidence of cholestasis, only one of these 31 experienced an unexplained increase in serum total bilirubin concentration during study, suggesting that normalizing plasma amino acid concentrations and/or providing taurine during parenteral nutrition may decrease the incidence of cholestasis associated with this therapy.

Ethotoin is an anticonvulsant that was considered minimally effective when introduced, but due to its apparent lack of side effects, there has been renewed interest in the drug for use in generalized and psychomotor seizures. We have characterized the pharmacokinetics of ethotoin in children and have found nonlinearity. Seizures were controlled in 16 of 17 patients, and there were no side effects reported. Gingival hyperplasia due to previous phenytoin therapy improved in all cases.

Fourteen infants requiring long-term total parenteral nutrition but able to tolerate small quantities of enteral feedings were randomized into carnitine treatment and placebo control groups. All infants had received nutritional support devoid of carnitine. Plasma carnitine levels and observed plasma lipid indices were not different before supplementation. Under standardized, steady-state conditions, 0.5 g/kg fat emulsion (intralipid) was administered intravenously over 2 hours both before and after infants received 7 days of continuous nasogastric or gastric tube L-carnitine (50 mumol/kg/day) or placebo. Plasma triglyceride, free fatty acid, acetoacetate, beta-hydroxybutyrate, and carnitine concentrations were observed at 0 (start of lipid infusion), 2, and 4 hours for pre- and post-treatment periods, and in addition at 6 and 8 hours after carnitine supplementation. Infants receiving carnitine had significantly greater beta-hydroxybutyrate plasma concentrations (P less than 0.05) and carnitine (P less than 0.001) at 0, 2, 4, 6, and 8 hours, and greater plasma acetoacetate concentrations (P less than 0.05) at 2, 4, 6, and 8 hours, compared with controls. Twenty-four-hour urinary carnitine excretion was very low for both groups before supplementation; after supplementation, excretion was higher (P less than 0.05) in the carnitine group. No significant differences were found between groups for plasma triglyceride or free fatty acid concentrations at any observation period. This study demonstrated enhanced fatty acid oxidation, as evidenced by increased ketogenesis, with L-carnitine supplementation in infants receiving long-term total parenteral nutrition.

The relationships among plasma total carnitine concentration, postnatal age, and fatty acid metabolism were evaluated in 57 infants receiving parenteral nutrition. Concentrations of plasma carnitine, triglycerides, free fatty acids, acetoacetate, and beta-hydroxybutyrate were determined before and at 2 and 4 hours from the beginning of a standardized 2-hour lipid infusion. Plasma carnitine concentrations declined with increasing postnatal age. There were no significant differences in gestational age or triglyceride concentrations between infants less than or equal to 4 weeks of age and those greater than 4 weeks of age, whereas free fatty acid concentrations were lower and acetoacetate and beta-hydroxybutyrate concentrations were higher in the younger infants. Infants less than or equal to 4 weeks of age were further grouped according to plasma carnitine concentration greater than 13 nmol/ml (group 1) and less than or equal to 13 nmol/ml (group 2) and were then compared with infants greater than 4 weeks of age (group 3). There were no significant differences in triglyceride concentrations among the three groups; free fatty acids, acetoacetate, and beta-hydroxybutyrate concentrations for group 2 patients were similar to those of group 1 patients or fell between values for group 1 and group 3 patients. These results demonstrate decreasing plasma carnitine concentrations and possibly for more than 4 weeks.

The clinical contribution and cost effectiveness of pharmacist involvement in peripheral-vein total parenteral nutrition (TPN) in a neonatal intensive-care unit was studied. Fourteen neonates who received a standardized TPN solution without pharmacist monitoring (Group 1) were compared with 14 neonates who received an individualized TPN solution with pharmacist monitoring (Group 2). Infants were excluded from the study if they received oral feeding, or TPN for less than five days, or were fluid-restricted. No significant difference in mean gestational age, birth weight, gestational size, age at initiation of therapy, duration of therapy, or daily amount of fluid administered was found between the two groups. The mean weight gain in Group 1 (4.9 g/day) was significantly less than in Group 2 (11.8 g/day) (p less than 0.02). The amount of protein provided to Group 2 (2.2 g/kg/day) was significantly greater than to Group 1 (1.9 g/kg/day) (p less than 0.01). The number of calories provided per day was greater for Group 2 (63 kcal/kg/day) than for Group 1 (53 kcal/kg/day) (p less than 0.001). When only those infants who received lipids were analyzed, Group 2 received significantly more lipid (2.0 g/kg/day) than group 1 (1.5 g/kg/day) (p less than 0.001). The mean daily cost was greater for Group 2; however, when cost was related to efficacy, Group-2 cost per gram of weight gain was lower than Group-1 cost. Pharmacist monitoring of an individualized program of TPN in neonates provided a greater mean daily weight gain, allowed a greater amount of nutrients to be provided, and was cost effective compared with the use of a standardized solution without pharmacist monitoring.

We have measured immunoglobulin (Ig) synthesis by circulating lymphoid cells of 20 patients with cirrhotic hyperglobulinemia (CH) and 20 age-matched controls. We used specific anti-Ig antisera to precipitate Ig synthesized from [14C] amino acid precursors in 13 controls and employed an electroimmunoassay of the "rocket" type to measure Ig elaborated by cultured cells in 4 patient-control pairs. In addition, we studied 3 patient-control pairs by absorption of elaborated Ig onto an anti-Ig-coated solid phase, bromoacetylcellulose. The synthetic index (SI; the ratio of Ig synthesis by a CH patient and a control) was elevated in every case. Mean SI by coprecipitation was 7.2 +/- 5.4 (mean +/- SD), by rocket" 7.3 +/- 3.0 for IgG and 2.2 +/- 0.8 for IgA, and by immunoabsorption 13.8 +/- 8.4 for IgG. Three cirrhotic nonhyperglobulinemic patient-control pairs showed a mean SI of 1.0 +/- 0.1. CH and control populations showed equal numbers of membrane Ig-positive B lymphocytes by immunofluorescence. We conclude that (1) peripheral blood lymphoid cells are appropriate for study of differences in Ig synthetic capacity among individuals; (2) CH is associated with increased in vitro Ig synthesis; and (3) CH lymphocytes may be an appropriate cell population for the study of control mechanisms in Ig synthesis.

Fifteen neonates requiring parenteral nutrition with lipid emulsion were given a 1.0 g/kg dose of safflower oil emulsion to evaluate triglyceride (TGY) and free fatty acid clearance. The dose was infused intravenously over 4 hr, and serum was obtained at 0, 2, 4, 6, and 8 hr. Peak serum TGY averaged 592 mg/dl for the appropriate for gestational age newborns and 606 mg/dl for the small for gestational age babies. The small for gestational age neonates had significantly higher serum free fatty acids at 2 and 4 hr into the infusion than did the appropriate for gestational age infants. Peak serum free fatty acids ranged from 0.915 to 3.233 mM in the appropriate for gestational age babies and 2.518 to 3.586 mM in the small for gestational age infants. In contrast to previous work with soybean oil emulsion, we did not demonstrate differences in TGY clearance between small for gestational age and appropriate for gestational age neonates and did demonstrate a markedly elevated serum TGY in these critically ill newborns. Serum TGY and free fatty acids must be monitored in newborns administered intravenous fat emulsion to avoid the complications of iatrogenic hyperlipemia.

There has been much concern about impaired immune function in children receiving infused lipid emulsions. Immunologic studies were carried out on 15 infants maintained on parenteral nutrition with intravenous safflower oil emulsion as part of the infusate. Significant increases in percentage rosette formation, total circulating T-cells, and mitogenesis to phytohemagglutinin and pokeweed mitogen were demonstrated after only 1 wk of lipid infusion. Additional parenteral nutrition did not further increase any immunologic parameter. These results suggest that infused safflower oil emulsion does not adversely alter cellular immune function.

Twelve infants with underlying gastrointestinal tract disorders receiving 16 courses of total parenteral nutrition were retrospectively studied. Stratification according to calorie intake provided the best means for discriminating among different outcomes. Infants receiving greater than 110 calories/kg/d experienced significantly greater increases in weight, mid-arm muscle circumference, and triceps and subscapular skinfold thicknesses than did infants receiving less than 110 calories/kg/d. Catch-up growth was only seen in infants with intakes of greater than 110 calories/kg/d. In nine of these 12 infants, in vitro cellular immune parameters were assayed. Infants in both the high- and low-calorie groups experienced similar increases in transformational responses to pokeweed mitogen (PWM) and phytohemagglutinin (PHA) and in the percentage of peripheral blood T lymphocytes. No increase in serum albumin was seen regardless of calorie intake.

A human colon cancer cell line, HCT-8, is shown to be an appropriate target cell for study of natural killer (NK) activity in man. In parallel experiments, effector cell characteristics for NK and antibody-dependent cellular cytotoxicity (ADCC) were found to be vested in a single lymphocyte subpopulation, which bore receptors for the Fc fragment of IgG, but lacked other surface receptors. The effector cell failed to adhere to glass and was inactivated by exposure to 3500 rad x-irradiation. Cells forming rosettes with SRBC and cells bearing receptors for complement were inactive in both systems. A wide distribution of NK activity was noted among individuals that correlated with the distribution of effector cell activity in ADCC (r = 0.8). Preincubation of NK effector cells with antibody-coated ADCC target cells markedly reduced NK activity. Neuraminidase treatment of effector cells led to increased NK and diminished ADCC, while trypsin treatment led to reduced NK activity and showed no effect on ADCC. Thus, NK and ADCC effector cells are highly overlapping if not identical populations, but different structures on the cell membrane may mediate the two activities.