Stability of 4 Intravenous Drug Formulations in Prefilled Syringes Stored Frozen for Up to 60 Days.

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.

Carnitine supplementation in premature neonates: effect on plasma and red blood cell total carnitine concentrations, nutrition parameters and morbidity.

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.

Relative bioavailability of carnitine supplementation 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.

Plasma amino Acid concentrations in 108 children receiving a pediatric amino Acid formulation as part of parenteral nutrition.

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.

Protein and nitrogen metabolism changes following closed head injury or cardiothoracic surgery in pediatric patients.

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.