Aluminum Effects in Infants and Children.

Aluminum has no known biological function; however, it is a contaminant present in most foods and medications. Aluminum is excreted by the renal system, and patients with renal diseases should avoid aluminum-containing medications. Studies demonstrating long-term toxicity from the aluminum content in parenteral nutrition components led the US Food and Drug Administration to implement rules for these solutions. Large-volume ingredients were required to reduce the aluminum concentration, and small-volume components were required to be labeled with the aluminum concentration. Despite these rules, the total aluminum concentration from some components continues to be above the recommended final concentration. The concerns about toxicity from the aluminum present in infant formulas and antiperspirants have not been substantiated but require more research. Aluminum is one of the most effective adjuvants used in vaccines, and a large number of studies have documented minimal adverse effects from this use. Long-term, high-concentration exposure to aluminum has been linked in meta-analyses with the development of Alzheimer disease.

Certification of Ochratoxin A Reference Materials: Calibration Solutions OTAN-1 and OTAL-1 and a Mycotoxin-Contaminated Rye Flour MYCO-1.

Background: Among the regulated mycotoxins that contaminate global food supplies, ochratoxin A is particularly harmful as a nephrotoxin and suspected carcinogen. Objective: To support global measurement comparability, certified calibration solutions for ochratoxin A and [13C6]-ochratoxin A (OTAN-1 and OTAL-1, respectively) as well as a mycotoxin-contaminated rye flour certified reference material (CRM) known as MYCO-1 were developed. Methods: Quantitative proton NMR was used along with maleic acid as an external standard traceable to the Système international (SI) to measure the concentration of ochratoxin A and [13C6]-ochratoxin A for the calibration solutions. OTAN-1 and OTAL-1 were then used as a pair in double isotope dilution MS to certify the mass fraction of ochratoxin A in MYCO-1. The natural ochratoxin A CRM served as the primary standard for traceable quantitation, while the synthetic [13C6]-ochratoxin A CRM served as the internal standard. Results: The certified mass fraction of ochratoxin A or [13C6]-ochratoxin A in the two mycotoxin calibration solution standards was established to be 11.03 ± 0.32 µg/g (k = 2) for OTAN-1 and 4.89 ± 0.18 µg/g (k = 2) for OTAL-1. The mass fraction of ochratoxin A in the rye flour standard MYCO-1 was certified at 4.05 ± 0.88 µg/kg (k = 2). Conclusions: These CRMs will support regulatory testing as they can be used in the method development, validation, calibration, and QC analysis of ochratoxin A. Highlights: This report highlights the methods used to certify OTAN-1, OTAL-1, and MYCO-1 as well as the challenges associated with producing such materials, which can be applied to a wide variety of other CRMs.

Applicability of papain solutions in immunohematology.

OBJECTIVE: To compare the enzyme activity of different presentations of papain solution to validate in-house preparations. METHODS: Two papain solutions were prepared, and the third presentation was a commercial solution. Tests were carried out with samples of red cells typed as weak RhD. RESULTS: In-house prepared papain solutions showed similar enzyme reactivity, and statistically no differences compared to the enzyme activity of the commercial solution. CONCLUSION: Evaluating the cost-benefit ratio, the in-house prepared papain solutions present more economic advantages, and can be incorporated into immunohematological routines as a way to cope with periods of financial crisis and cost-containment policies.

Testing the validity of reference standard materials and stock solutions of veterinary drugs using LC-MS/MS.

This paper reports a practical approach for the stability testing of 37 veterinary drugs in stock standard solutions stored at -20°C for 1-3 years and the study of expiry date extension of 7 expired reference standard materials stored at 4°C. Stored stock solutions were compared versus freshly prepared stock solutions and concentrations determined using LC-MS/MS. The validity of expired reference materials was tested by new valid reference materials. LC-MS/MS method and parameters were optimised to get the maximum signal stability of the analytes. Statistical analysis was developed and performed to evaluate the stability results according to the acceptability criteria of 10% set by the European Commission guidance document SANTE/11813/2017. The stability of most of the stock solutions of the following veterinary drug families: ß-agonists, illegal dyes, inhibitors, macrolides, penicillins, quinolones, sulfonamides and tetracyclines ranged from 12 to 36 months. ß-Agonist compounds have the maximum stability period of 36 months while penicillin's stock solution in methanol showed the least stability. The results of testing the expiry date extension of reference standard materials demonstrated that there was no any deterioration of all tested compounds after manufacturer expiry date by 4-7 years.

Applicability of papain solutions in immunohematology / Aplicabilidade de soluções de papaína em imuno-hematologia

ABSTRACT Objective: To compare the enzyme activity of different presentations of papain solution to validate in-house preparations. Methods: Two papain solutions were prepared, and the third presentation was a commercial solution. Tests were carried out with samples of red cells typed as weak RhD. Results: In-house prepared papain solutions showed similar enzyme reactivity, and statistically no differences compared to the enzyme activity of the commercial solution. Conclusion: Evaluating the cost-benefit ratio, the in-house prepared papain solutions present more economic advantages, and can be incorporated into immunohematological routines as a way to cope with periods of financial crisis and cost-containment policies.

RESUMO Objetivo: Comparar a atividade enzimática de diferentes apresentações de solução de papaína para validação de preparados in-house. Métodos: Foram preparadas duas soluções de papaína, e a terceira apresentação tratou-se de uma solução comercial. Os testes comparativos das reações enzimáticas foram realizados com amostras de hemácias tipadas como RhD fraco. Resultados: As soluções de papaína preparadas in-house apresentaram reatividade enzimática semelhante e estatisticamente sem diferenças em comparação com a atividade enzimática da solução comercial. Conclusão: Avaliando-se a relação entre custo e benefício, as soluções de papaína preparadas in-house são economicamente vantajosas, podendo ser incorporadas às rotinas imuno-hematológicas como forma de enfrentamento em períodos de crise financeira e em políticas de retenção de gastos.

Use of potassium adsorption filter for the removal of ammonia and potassium from red blood cell solution for neonates.

BACKGROUND: Ammonia in the plasma usually does not pass through the blood-brain barrier (BBB). However, it can affect the brain as a neurotoxin in neonates with anemia of prematurity. Excess intake of ammonia should therefore be restricted in conditions involving BBB breakdown, such as in premature neonates. A potassium adsorption filter (PAF) can remove not only potassium, but also ammonia from red blood cell (RBC) solution. PAF for neonates (PAF-n) has been recently introduced using small satellite packs. We evaluated the effects of PAF-n on the removal of ammonia and potassium from RBC solution in small satellite packs. STUDY DESIGN AND METHODS: RBC solutions were obtained from the Japanese Red Cross Society. Two units of RBC solution (280 mL) were divided into four satellite packs (70 mL/pack). The RBC solution was passed through PAF-n (Kawasumi Laboratories Inc.) that was primed with saline (100 mL) before use. The concentrations of ammonia and potassium were measured in the solution before and after filtration (four samples of 10 mL each of filtered RBC solution) by Biomedical Laboratories. RESULTS: Approximately 47 to 82 and 84% to 93% of ammonia and potassium were removed from the RBC solution, respectively, without dilution with saline. CONCLUSION: PAF-n can remove ammonia and potassium from RBC solution in small satellite packs. PAF-n could therefore improve the clinical prognosis of neonates with poorly developed BBB by limiting the delivery of excess ammonia found in the RBC solution.

Calcium Chloride and Calcium Gluconate in Neonatal Parenteral Nutrition Solutions without Cysteine: Compatibility Studies Using Laser Light Obscuration Methodology.

There are no compatibility studies for neonatal parenteral nutrition solutions without cysteine containing calcium chloride or calcium gluconate using light obscuration as recommended by the United States Pharmacopeia (USP). The purpose of this study was to do compatibility testing for solutions containing calcium chloride and calcium gluconate without cysteine. Solutions of TrophAmine and Premasol (2.5% amino acids), containing calcium chloride or calcium gluconate were compounded without cysteine. Solutions were analyzed for particle counts using light obscuration. Maximum concentrations tested were 15 mmol/L of calcium and 12.5 mmol/L of phosphate. If the average particle count of three replicates exceeded USP guidelines, the solution was determined to be incompatible. This study found that 12.5 and 10 mmol/L of calcium and phosphate, respectively, are compatible in neonatal parenteral nutrition solutions compounded with 2.5% amino acids of either TrophAmine or Premasol. There did not appear to be significant differences in compatibility for solutions containing TrophAmine or Premasol when solutions were compounded with either CaCl2 or CaGlu-Pl. This study presents data in order to evaluate options for adding calcium and phosphate to neonatal parenteral nutrition solutions during shortages of calcium and cysteine.

Stability study of veterinary drugs in standard solutions for LC-MS/MS screening in food.

A study on stability of veterinary drugs in standard solutions stored at -80°C and at -20°C was conducted over 1 year. Data were acquired on 152 individual stock standard solutions and also on 15 family mixes and 2 working standard solutions. All solutions were prepared, stored and compared 1 year later against freshly prepared ones by LC-MS/MS. A statistical analysis was performed to set the acceptability criteria, taking into account the variability of standard preparations. In individual stock standard solutions stored at -80°C (12 months) and -20°C (9 months), stability was demonstrated for 141 and 140 out of 152 compounds, i.e. for 92% and 93% of compounds, respectively. Drugs were even more stable when solubilised in either diluted family mixes or working standard solutions, with more than 99% and 94% of compounds found unaltered when stored at -80°C and at -20°C, respectively. In mixes, beta-lactams from the cephalosporin (cefadroxil and cephalexin) and penicillin (amoxicillin and ampicillin) families were found to be the least stable compounds when stored at -20°C (6 months), necessitating storage at -80°C to achieve a 1-year shelf life. The study also evidenced solubility issues for two sulfonamides (sulfadiazine and sulfamerazine) in methanol-based solutions. An independent stability study conducted by a second laboratory confirmed the 1-year stability of 3 family mixes-quinolones, sulfonamides and tetracyclines.

Product standardisation as a tool to control prescribing costs - a case study of alginate liquid preparations.

INTRODUCTION: Product standardisation involves promoting the prescribing of pre-selected products within a particular category across a healthcare region and is designed to improve patient safety by promoting continuity of medicine use across the primary/secondary care interface, in addition to cost containment without compromising clinical care (i.e. maintaining safety and efficacy). OBJECTIVES: To examine the impact of product standardisation on the prescribing of compound alginate preparations within primary care in Northern Ireland. METHODS: Data were obtained on alginate prescribing from the Northern Ireland Central Services Agency (Prescription Pricing Branch), covering a period of 43 months. Two standardisation promotion interventions were carried out at months 18 and 33. In addition to conventional statistical analyses, a simple interrupted time series analysis approach, using graphical interpretation, was used to facilitate interpretation of the data. RESULTS: There was a significant increase in the prescribed share of the preferred alginate product in each of the four health boards in Northern Ireland and a decrease in the cost per Defined Daily Dose for alginate liquid preparations overall. Compliance with the standardisation policy was, however, incomplete and was influenced to a marked degree by the activities of the pharmaceutical industry. The overall economic impact of the prescribing changes during the study was small (3.1%). CONCLUSION: The findings suggested that product standardisation significantly influenced the prescribing pattern for compound alginate liquid preparations within primary care across Northern Ireland.

Comparative study of blood collection tubes and thromboplastin reagents for correction of INR discrepancies: a proposal for maximum allowable magnesium contamination in sodium citrate anticoagulant solutions.

International normalized ratio (INR) discrepancies were noted between clinical laboratories using various prothrombin time (PT) systems. We studied the influence of different commercial blood collection tubes and different PT systems on INR measurements. INRs of fresh patient samples were determined by 3 laboratories, each using different PT systems. In the first part of the study, samples were drawn with Vacutainer tubes and in the second part with Monovette tubes. In the first part of the study, the maximum bias for all patients amounted to 0.46 INR (14%), and in the second part, to 0.14 INR (4.9%). The maximum bias for all patients could be reduced further by local system calibration using frozen pooled plasma specimens. The sodium citrate solutions in the blood collection tubes were contaminated with magnesium ions (approximately 2.7 mmol/L and 0.3 mmol/L in the Vacutainer and Monovette, respectively). INR discrepancies could be explained largely by this influence of blood collection tubes. The maximum allowable magnesium contamination in sodium citrate anticoagulant solutions should be less than 1 mmol/L.

[Validation of pharmaceutical quality of a [6,6-(2)H(2)]-glucose parenteral solution used for insulin-resistance measurement during human clinical trials]. / Validation de la qualité pharmaceutique de préparations de [6,6-(2)H(2)]-glucose en solution aqueuse administrées par voie parentérale pour la mesure de l'insulino-résistance dans le cadre d'essais cliniques.

INTRODUCTION: Deuterated glucose ([6,6-(2)H(2)]-glucose) is a stable isotopic tracer administered parenterally in healthy volunteers, obese or diabetic patients in clinical trial to study glucose metabolism during euglycemic hyperinsulinemic clamps. In accordance with the Health Authorities on drug safety, we evaluated the pharmaceutical quality of this preparation for biomedical research with a stability study. METHODS: After pharmaceutical qualification of the raw material, the [6,6-(2)H(2)]-glucose was dissolved in water for injection, then sterile, filtered under positive pressure of nitrogen and then autoclaved. Two batch products (500mg/10mL and 2g/15mL) were sampled to evaluate glucose alteration, isotope shift, limpidity, apyrogenicity and sterility at regular intervals for 2 years. Deuterated glucose solutions were stored in the dark, at +2°C+8°C, in type II glass bottles. RESULTS: Neither significant decrease of glucose concentration nor pH variation were observed for 2 years. The 5-hydroxymethylfurfural concentration was below the human harmful levels, attesting a non-generation of metabolites during autoclaving. Isotopic enrichment higher than 99% reflected the stability of deuterated label on the 6-carbon of glucose molecules. The non-visible particle concentration below the minimal permissible concentration tolerated by the European Pharmacopoeia and the absence of bacterial endotoxin and bacterial growth attested limpidity, apyrogenicity and sterility of the [6,6-(2)H(2)]-glucose solutions. CONCLUSION: After the 2-year study, 500mg/10mL and 2g/15mL deuterated glucose solutions stored in the dark at +2°C+8°C were stable in aqueous solution, allowing to ensure safety administration for human clinical trials using euglycemic hyperinsulinemic clamps.

Factors affecting the concentration of electrolyte infusions prepared from stock solutions.

BACKGROUND: Wide variation in the concentrations of electrolyte infusions prepared from stock solutions has previously been reported. Layering of viscous stock electrolyte solutions in their diluent can lead to high concentrations being delivered during the infusion, resulting in potentially very serious medication errors which have caused deaths. OBJECTIVE: To determine the safest way of preparing homogenous electrolyte solutions for parenteral infusion. METHODS: The study examined how the concentration of potassium and magnesium varied during infusions after concentrated stock solutions had been diluted to 400 mmol/l with 0.9% sodium chloride. It also examined the use of syringes compared to polyvinyl chloride (PVC) bags, agitating vigorously with a 'vortex' mixer compared to inversion, and the influence of allowing the infusions to stand for 24 h before administration. The study was conducted in November 2009. Results It was found that, in general, the concentrations of potassium and magnesium solutions are less variable if they are prepared in PVC bags rather than syringes. Vigorous mixing of concentrated stock solutions with diluent and allowing preparations to stand for 24 h also improved the homogeneity of the infusions. However, even with meticulous preparation, some infusions deviated from the expected concentration by more than 10%. CONCLUSION: It is recommended that electrolyte infusions are prepared and provided by the pharmaceutical industry in prefilled syringes or bags. Given the likely cost of these products, an alternative would be to prepare infusions in pharmacy in advance, using PVC bags rather than syringes, and that they should be agitated vigorously with a 'vortex' mixer.

Variación en el uso de nutrición parenteral en un hospital infantilen Madrid (España) a lo largo de 15 años / Evolution of paediatric parenteral nutrition over the last 15 years in a tertiary hospital in Madrid (Spain)

Objetivo: Analizar el empleo de la nutrición parenteral (NP) pediátrica en un hospital terciario en Madrid (1994-2008). Material y métodos: Se revisaron las historias clínicas de pacientes pediátricos hospitalizados con NP en 2008, comparándose con 2002 y 1994. Resultados: Recibieron NP 120, 78 y 71 niños, siendo el 1,6%, 1,3% y 1,0% respectivamente del total de ingresados (2008, 2002 y 1994). Hubo diferencias significativas en la composición en el primer día en kilocalorías y lípidos; pero no en volumen, carbohidratos ni aminoácidos. La cirugía gastrointestinal fue la indicación más frecuente. La duración media de la NP varió de 15,2 ± 14,8 (1994) a 11 ± 9,8 días (2008) (p < 0,05). Presentaron complicaciones el 24,8% (2008), 10,8% (2002) y 16,9% (1994) de los pacientes. Conclusiones: En número absoluto y relativo de NP ha aumentado durante los años evaluados, aunque la duración media se ha reducido significativamente. Las complicaciones, sin embargo, han aumentado (AU)

Objective: To analyze the use of paediatric parenteral nutrition (PN) in a tertiary level hospital in Spain (1994-2008). Materials and methods: The charts from infants and children receiving NP in 2008 were reviewed. Data were compared with those in 1994 and 2002. Results: 120 patients received PN, 78 and 71 corresponding to 1.6%, 1.3% and 1.0% of total admissions in 2008, 2002 and 1994 respectively. When composition of PN was compared in the first day we found significant differences in energy and lipids; but not in volume, carbohydrate, or amino acid composition. Gastrointestinal surgery was the most common indication. Mean length was 11.0 ± 9.8 days (2008) to 15.2 ± 14.8 (1994) (p < 0.05). Complications were present in 24.8 patients (2008), 10.8% (2002) and 16.9 (1994). Conclusions: PN use increased along the study period, although mean length decreased. There were more complications in 2008 than in previous years (AU)

Evaluación de nutrición parenteral estandarizada en niños / Assessment of standard parenteral nutrition in children

Introducción: En la actualidad existe un mayor consenso en el proceso de soporte nutricional con Nutrición Parenteral (NP) en pediatría, en los estándares de la prescripción, formulación, elaboración y en los requerimientos nutricionales, para mejorar la calidad del proceso y seguridad en el paciente. La utilización de soluciones estandarizadas de NP en niños es minoritaria por la dificultad de adaptación a las distintas situaciones fisiopatológicas. Para hacerlo viable, en el 2006 diseñamos y validamos un amplio rango de soluciones estandarizadas para niños mayores de 10 kg y/o mayores de 1 año. Objetivo: Evaluar la utilización e idoneidad de las soluciones de NP estandarizadas en un Hospital de Tercer Nivel desde su implantación. Método: Analizamos todas las prescripciones y formulaciones de NP de los niños desde enero de 2006 hasta junio de 2008: la frecuencia de prescripción de soluciones estándar según edad, peso e indicación y sus modificaciones. Comparamos los nutrientes aportados con las soluciones NP individualizados frente a las recomendaciones de las Guías de referencia y las NP estandarizadas. Resultados: 47 niños con un peso medio de 26,6 kg (9-50) y edad media 6,8 años (1-14) recibieron 539 unidades de NP. Las NP estandarizadas (437) fueron utilizadas en el 83% de los pacientes. Sus requerimientos totales energéticos se alcanzaron de1 a 3 días , utilizando de una a tres tipos fórmulas . De ellas solo tuvieron modificación un 4% (22), con cambios fácilmente aplicables : aumento del volumen (16), disminución de la glucosa (3), y aumento del potasio (3). El análisis de las NP individualizadas en 8 niños, muestran una misma tendencia, menor aporte calórico en un 33% al recomendado. Conclusión: Las soluciones de PN estandarizadas se adecuaron a las necesidades nutricionales de la mayoría de los pacientes, según su estado y patología, destacando su adaptabilidad y versatilidad. Su utilización, ha agilizado el circuito prescripción-validación-preparación y ha mejorado la eficiencia del proceso (AU)

Introduction: Nowadays, there is a stronger consensus on the proceedings of nutritional support with parenteral nutrition (PN) in paediatrics, the prescription standards, its formulation, elaboration, and nutritional requirements in order to improve the process quality and the patient's safety. The use of standardized PN solutions in children is rare due to the difficulty to adapt them to every pathophysiologic condition. In order to do so, in 2006 we designed and validated a big range of standard solutions for children weighing more than 10 kg or being older than 1 year. Objective: To assess the use of standard PN solutions and their suitability in children from January of 2006 until June of 2008: the frequency of prescription of standard solutions by age, weight, and indication, as well as their modifications. We compared the nutrients given by individualized PN solutions versus the recommendations of the Reference Guidelines and standardised PN. Results: 47 children with a mean weight of 26.6 kg (9-50) and mean age 6.8 years (1-14) received 539 units of PN. Standardized PN (437) were used in 83% of the patients. Their total energy requirements were reached within 1-3 days by using one to three types of formulas. Only 4% (22) of them were modified, with easily feasible changes: volume increase (16), glucose lowering (3), and potassium increase (3). The analysis of the individualized PN in 8 children shows the same trend, with a caloric intake lower than 33% of the recommended one. Conclusion: Standardized PN meet the nutritional requirements in most of the patients according to their morbid condition, highlighting their adaptability and versatility. Their use has eased the prescription-validation-preparation circuit and has improved the efficiency of the process (AU)

Growth of microorganisms in total parenteral nutrition solutions without lipid.

BACKGROUND: To identify the microorganisms that can grow rapidly in total parenteral nutrition (TPN) solutions, we investigated the growth of the major causes of catheter-related blood stream infection (Staphylococcus aureus, Serratia marcescens, Bacillus cereus, and Candida albicans) in TPN solutions without lipid. METHODS: Experiment 1: A commercial TPN solution without lipid containing multivitamins (pH5.6) was used. A specific number of each test microorganism was added to each 10 mL of the TPN solution and incubated at room temperature. An aliquot of test solution was sampled and inoculated to SCD agar plates at 0, 24, and 48 hrs after the addition of the microorganisms. The number of microorganisms was counted as colony forming units. Experiment 2: The other 2 commercial TPN solutions without lipid (pH5.5) were supplemented with multivitamins. The pH values of the solutions were adjusted to about 6.0, 6.5, or 7.0 using 0.5 mol/L NaOH. The addition of microorganisms, incubation, and counting were performed in the same manner. RESULTS: Experiment 1: S. aureus, S. marcescens, and B. cereus did not increase in the TPN solution without lipid containing multivitamins (pH5.6), but C. albicans increased rapidly. Experiment 2: The 3 bacterial species did not increase even at pH6.0, but increased at pH6.5 and increased rapidly at pH7.0 in both TPN solutions. C. albicans increased similarly at any pH. CONCLUSION: These results suggest that bacterial species cannot grow in TPN solutions without lipid due to the acidity (pH5.6 or lower), but Candida species can grow regardless of the acidity.

Detection of Rh antibodies using two low ionic diluents: extension of the incubation time and the number of Rh antibodies detected.

BACKGROUND: Low ionic strength solution (LISS) is used to increase the rate of association of antibody to the corresponding antigen during antibody detection tests. A number of LISSs are available on the market. AIMS: The efficiency of two commercial low ionic diluents, DiaMed ID-CellStab and Inverclyde LISS were assessed using the DiaMed-ID LISS Coombs microtube column system and an incubation time varying from 15 to 35 min. MATERIALS AND METHODS: One-hundred samples containing five Rh antibodies (anti-D, anti-C, anti-E, anti-c and anti-e) were tested against commercial red cells using the two low ionic diluents after 15, 25 and 35 min. RESULTS: The Inverclyde LISS detected 91, 95 and 96% of the Rh antibodies compared to 78, 79 and 83% for ID-CellStab after 15, 25 and 35 min incubation time, respectively, for both methods. CONCLUSIONS: The Inverclyde LISS is a more suitable and efficient diluent than ID-CellStab for the detection of Rh antibodies. The sensitivity of Rh antibody detection increased for the both methods as the incubation time increased.