Electron Microscopy for the Stability Assessment of Parenteral Nutrition Admixtures: Focus on Precipitation.

(1) Background: parenteral nutrition (PN) is indispensable for patients unable to receive oral or enteral feeding. However, the complexity of PN solutions presents challenges regarding stability and compatibility. Precipitation reactions may occur. The most frequent is the formation of calcium phosphate (Ca-P). The different factors influencing these reactions must be considered to ensure patient safety. (2) Methods: eight paediatric PN solutions were prepared, following standard protocols. Samples were stored at room temperature and in a refrigerator. Electron microscopy, coupled with energy dispersive X-ray spectroscopy (EDS), was employed. Precipitates were analysed for composition and morphology. (3) Results: precipitates were observed in all samples, even at day 0. Crystalline structures, predominantly composed of calcium or magnesium, sometimes associated with chlorine or phosphorus, were detected. Additionally, amorphous precipitates, contained heterogeneous compositions, including unexpected elements, were identified. (4) Conclusions: various precipitates, primarily calcium- or magnesium-based, can form in PN solutions, although it is not expected that they can form under the real conditions of use. Calcium oxalate precipitation has been characterised, but the use of organic calcium and phosphate salts appears to mitigate calcium phosphate precipitation. Electron microscopy provides interesting results on NP precipitation, but sample preparation may present technical limitations that affect the interpretation of the results.

Compatibility studies of selected multichamber bag parenteral nutrition with fluconazole.

OBJECTIVE: Fluconazole (FLZ) is a drug widely used in the treatment of fungal infections including the treatment of immunocompromised patients, HIV-infected patients, and cancer patients. Critically ill patients often require the administration of drugs with parenteral nutrition (PN). The safety of this combination should be defined before the drug and PN are administered in one infusion line. This study aimed to determine the compatibility of FLZ with six selected multichamber bag parenteral nutrition. METHODS: FLZ solution for infusion was combined with PNs in appropriate proportions, considering most clinical situations resulting from different possible administration rates of the preparations. Samples were visually assessed, and pH, osmolality, turbidity, particle size (dynamic light scattering and light obscuration methods), and zeta potential were measured. These measurements were made immediately after combining the solutions and after 4 h of storage at 23 ± 1°C. RESULTS: FLZ combined with PNs did not cause changes observed visually. The turbidity of the samples was <0.4 NTU. The average particle size of the lipid emulsion was below 300 nm, and the PFAT5 parameter was ≤0.02%. The absolute value of the zeta potential of the PN + FLZ samples was higher for 5 out of 6 PN than the corresponding value for PN immediately after activation. Changes in pH and osmolality during 4 h of sample observations were within acceptable limits. CONCLUSION: Compatibility of the FLZ with six multichamber bag PN was confirmed. Hence, those preparations can be administered to patients in one infusion line using the Y-site.

Stability and compatibility of parenteral nutrition solutions; a review of influencing factors.

Both stability and compatibility of parenteral nutrition solutions (PNS) with drug products are major concerns for clinicians and clinical pharmacists, especially when concurrent administration of PNS with intravenous medications (IVM) is unavoidable. Since the same physicochemical principles apply to both adult's and paediatrics' PNS, concerns about stability and compatibility may still apply to both. However, these concerns are relatively more common in paediatrics and neonatal clinical settings, where limited vascular access can be problematic and the coadministration of PNS and drugs is more common. In neonatal and paediatric populations, there have been few experimental studies and comprehensive evaluations looking at medication compatibility with frequently used PNS. This work is part of a larger research project concerned for compatibility of PNS with commonly used intravenous medication in paediatric and neonates. This paper captures and reviews published data on factors influencing stability and compatibility of parenteral nutrition solutions. This information will help clinicians and clinical pharmacists to understand the principals of the stability and compatibility of PNS, furthermore, it will inform better design of future compatibility studies, as it highlights the complexity of PNS and the multiple factors influencing the stability of PNS, and hence its compatibility with IVM. When preparing, prescribing, and administering the PNS, especially when co-administration with IVM is unavoidable, it is important to take into account the physicochemical properties of the PNS components and IVM as well as administration conditions and environmental factors. These factors should also be considered in the design of the compatibility studies of the PNS with the IVM.

One-chamber and two-chamber parenteral nutrition admixtures for pediatric and adult patients: An evaluation of physico-chemical stability at room and cold temperature.

OBJECTIVES: The aim of this study was to evaluate the physico-chemical stability of compounded total parenteral nutrition admixtures through peroxidation assay and ultraviolet-visible spectroscopy, high-performance liquid chromatography analysis, nuclear magnetic resonance spectrometry, pH meter, and dynamic light scattering. METHODS: The present study considered parenteral nutrition (PN) admixtures for pediatric and adult patients. The admixtures were characterized by a high content of vitamins and trace elements. They were prepared in one- or two-chamber bags in the hospital pharmacy using an automatic compounding system in a sterile room with laminar airflow at different temperature conditions and light exposure. The experiment setup comprised fat emulsions, lipid-free PN solutions, and single-chamber bags before and after adding vitamins and trace elements. The stability at room temperature (+25°C) and cold temperature (+2-8°C) was assessed by various means. RESULTS: Two-compartment admixtures, single-chamber bags, and all-in-one PN supplemented with vitamins and trace elements are stable up until 35, 9, and 7 d, respectively, when protected from light and stored at +2 to 8°C. Also, the supplemented single-chamber PN was found to be stable up to 48 h when stored at +25°C with light exposure. CONCLUSIONS: The results obtained will help improve PN management at the compounding center and in hospital wards, because they allow for the extension of the validity time frame provided so far by the different formulations and, therefore, therapy scheduling over several days.

Parenteral Nutrition Overview.

Parenteral nutrition (PN) is a life-saving intervention for patients where oral or enteral nutrition (EN) cannot be achieved or is not acceptable. The essential components of PN are carbohydrates, lipids, amino acids, vitamins, trace elements, electrolytes and water. PN should be provided via a central line because of its hypertonicity. However, peripheral PN (with lower nutrient content and larger volume) can be administered via an appropriate non-central line. There are alternatives for the compounding process also, including hospital pharmacy compounded bags and commercial multichamber bags. PN is a costly therapy and has been associated with complications. Metabolic complications related to macro and micronutrient disturbances, such as hyperglycemia, hypertriglyceridemia, and electrolyte imbalance, may occur at any time during PN therapy, as well as infectious complications, mostly related to venous access. Long-term complications, such as hepatobiliary and bone disease are associated with longer PN therapy and home-PN. To prevent and mitigate potential complications, the optimal monitoring and early management of imbalances is required. PN should be prescribed for malnourished patients or high-risk patients with malnutrition where the feasibility of full EN is in question. Several factors should be considered when providing PN, including timing of initiation, clinical status, and risk of complications.

High particle counts in neonatal parenteral nutrition solutions with added cysteine: Relationship to crystal formation and effect of filtration on cysteine content.

BACKGROUND: Parenteral nutrition(PN) solutions containing calcium gluconate and cysteine have elevated particle counts when analyzed using laser light obscuration (LO) as recommended by the United States Pharmacopeia. It is unclear whether increased particle formation in these solutions results in decreased availability of cysteine to neonatal patients due to filtration. OBJECTIVE: The purpose of this study was to measure cysteine concentrations in neonatal PN solutions before and after filtration as well as analyze precipitates on filters. METHODS: Solutions of PN containing amino acids with and without cysteine that were compounded with calcium chloride or calcium gluconate plus potassium phosphate were analyzed using LO. Concentrations of cysteine were measured before and after filtration. The effect on particle formation of magnesium sulfate (MgSO4 ) and D70 was also evaluated. RESULTS: Multiple additives including the specific calcium or D70 additive, cysteine, and MgSO4 influenced particle formation of particles detected using LO. There was no significant decrease in cysteine concentration because of filtering and there was no difference in the amount of calcium on filters of various solutions after filtration regardless of LO particle counts. Scanning electron micrographic (SEM) analysis found no significant differences in crystal composition. Light microscopic and SEM examination did not show evidence of high particle counts on filters. CONCLUSION: The increased particle counts detected in neonatal PN solutions containing cysteine added at the time of compounding does not appear to result in increased precipitate or crystal formation. It is not associated witha decrease in cysteine delivery to patients.

Sources of unintentional manganese delivery in neonatal parenteral nutrition.

BACKGROUND: Manganese (Mn) neurotoxicity is a concern in neonates receiving parenteral nutrition (PN). Prior studies have identified Mn contamination of PN ingredients as a source of daily Mn exposure from PN. This study was conducted to determine which neonatal PN ingredients are sources of this unintentional Mn delivery. METHODS: Mn concentration was measured in different lot numbers of individual PN ingredients using inductively coupled plasma-mass spectrometry. PN admixtures were then prepared using standard doses of the tested individual ingredients, and admixture Mn concentration was measured. RESULTS: Magnesium sulfate and calcium gluconate are the major contributors to hidden unintentional Mn exposure in neonatal PN. Maximum measured Mn concentrations in these two ingredients were 443 and 46.8 mcg/L, respectively. Sodium phosphate and potassium phosphate were the next highest at 40 and 24 mcg/L, respectively. Other ingredients contained a trivial or no measurable quantity of Mn. PN admixture Mn content was 16%-30% higher than predicted values based on individual ingredient Mn content. If infused at 150 ml/kg/day, a standard neonatal PN admixture with no added Mn is capable of unintentionally delivering up to 0.9 mcg/kg/day Mn. CONCLUSION: Neonatal PN without any added Mn provides close to the American Society for Parenteral and Enteral Nutrition (ASPEN)-recommended Mn dosage of 1 mcg/kg/day. This supports the potential utility of a Mn-omission approach to trace element provision in neonatal PN. Further studies are needed to test such an approach and to evaluate the clinical significance of unintended Mn delivery in neonates receiving PN.

[Neonatal parenteral nutrition formulation: where are we?] / Formulación de nutrición parenteral neonatal: ¿dónde estamos?

INTRODUCTION: Introduction: the introduction of parenteral nutrition in preterm infants has meant a major advance in their prognosis, being the last few years very fruitful in terms of publication of guidelines in this area. Objectives: to know the formulation and preparation procedures of neonatal parenteral nutrition (NPN) in Spanish hospitals. Methods: a multi-centre survey was conducted in Pharmacy Services on the aforementioned processes. Results: fifty-five hospitals met inclusion criteria. Electronic prescription systems were use by 51 %, 65.5 % always formulated individually, while 34.4 % had predesigned formulas. Tricameral preparations were used by 13.0 %. In 52.7 % of cases, first day nutrition was prepared on demand, starting before 8 hours of life in 88.1 % of cases. Inorganic phosphate was the first option in 10.4 %, vitamins, trace elements and zinc were added daily in 92.7 %, 90.9 % and 70.9 % of cases, respectively. NPN including lipids in the same bag was formulated by 45.4 % of the hospitals, compared to 34.5 % where it was administered separately in all cases. In 50.9 % of hospitals they never added heparin to their NPN. The 89.1 % used photoprotected bags. The stability of the admixture varied from 24 hours to 15 days. Conclusion: the elaboration of the PPN in Spain is subject to great variability. There is controversy regarding the use of heparin and ternary mixtures, which is reflected in the variability of clinical practice.

INTRODUCCIÓN: .Introducción: la instauración de nutrición parenteral al prematuro ha supuesto un importante avance en su pronóstico. Los últimos años han sido muy fructíferos en cuanto a la publicación de guías en este ámbito. Objetivos: conocer los procedimientos de formulación y elaboración de las nutriciones parenterales neonatales (NPN) en los hospitales españoles. Métodos: se llevó a cabo una encuesta multicéntrica dirigida a los servicios de farmacia sobre los procesos anteriormente citados. Resultados: 55 hospitales cumplieron criterios de inclusión. El 51 % disponía de sistemas informáticos de prescripción, y el 65,5 % formulaba siempre de forma individualizada, mientras que el 34,4 % disponía de fórmulas prediseñadas. Los preparados tricamerales eran utilizados por el 13,0 %. En el 52,7 % de los casos se preparaban las nutriciones de primer día bajo demanda, y ésta se iniciaba antes de las 8 horas de vida en un 88,1 % de los casos. El fosfato inorgánico era la primera opción en un 10,4 %. Se añadían diariamente vitaminas, oligoelementos y zinc en el 92,7 %, 90,9 % y 70,9 % de los casos, respectivamente. El 45,4 % de los hospitales elaboraba siempre las NPPN incluyendo los lípidos en la misma bolsa, frente al 34,5 % en los que estos se administraban por separado en todos los casos. El 50,9 % de los hospitales nunca añadía heparina a sus nutriciones. Las bolsas fotoprotectoras eran utilizadas por un 89,1 %. La estabilidad de las nutriciones variaba desde 24 horas a 15 días. Conclusiones: la elaboración de la NPN en España está sujeta a gran variabilidad. Existe controversia respecto al uso de heparina y mezclas ternarias, reflejada en la variabilidad de la práctica clínica.

[Effectiveness and safety of two lipid emulsions for parenteral nutrition in postsurgical critically ill patients: Clinoleic® versus SMOFlipid®]. / Eficacia y seguridad de dos emulsiones lipídicas de nutrición parenteral en pacientes críticos posquirúrgicos: Clinoleic® frente a SMOFlipid®.

INTRODUCTION: Introduction: a lipid emulsion (LE) may result in different immunomodulatory effects depending on its fatty acid composition. LEs enriched with fish oil and those based on olive oil (OOBE) have shown advantages over those derived from soybean oil, although very few studies have compared these with each other, and none was performed in critically ill surgical patients. Objectives: to demonstrate non-inferiority for the therapeutic efficacy of SMOFlipid® (enriched with fish oil) versus Clinoleic® (OOBE) in relation to the occurrence of nosocomial infection and other evolutionary parameters. To demonstrate non-inferiority in the safety profile of SMOFlipid® versus Clinoleic® in terms of mortality and adverse events. Material and method: a phase-III, non-inferiority clinical trial performed in critically ill postsurgical patients. The subjects were randomized to receive SMOFlipid® or Clinoleic®. For comparison of qualitative variables case frequencies and percentages were obtained using the Chi-squared test or Fisher's exact test. Means were compared between groups using Student's t-test. A p-value lower than 0.05 was considered statistically significant. The Farrington-Manning, Miettinen-Nurminen, and Gart-Nam tests were applied in the main non-inferiority analysis of the primary endpoint. Results: during de inclusion period 73 patients were selected, 37 of whom received Clinoleic® and 36 SMOFlipid®. Regarding the variable "decrease in nosocomial infections", SMOFlipid® proved to be non-inferior to Clinoleic®. Regarding the main variable "mortality", SMOFlipid® proved to be non-inferior to Clinoleic®. There were no statistically significant differences in the occurrence of adverse effects either. Conclusions: in our study, SMOFlipid® proved to be non-inferior to Clinoleic® in terms of efficacy and safety.

INTRODUCCIÓN: Introducción: las emulsiones lipídicas (EL) pueden asociar distintos efectos inmunomoduladores dependiendo de su composición de ácidos grasos. Las EL enriquecidas con aceite de pescado y las basadas en aceite de oliva (EBAO) han mostrado ventajas frente a las derivados del aceite de soja, aunque son muy escasos los estudios que las comparan entre sí y no existe ninguno en pacientes críticos quirúrgicos. Objetivos: Demostrar la no inferioridad de la eficacia terapéutica de SMOFlipid® (enriquecida con aceite de pescado) frente a Clinoleic® (EBAO) en relación con la aparición de infecciones nosocomiales y otros parámetros evolutivos. Demostrar la no inferioridad de la seguridad de SMOFlipid® frente a Clinoleic® expresada como aparición de mortalidad y acontecimientos adversos. Material y método: ensayo clínico de fase III, de no inferioridad, realizado en pacientes críticos posquirúrgicos. Los sujetos se aleatorizaron para recibir SMOFlipid® o Clinoleic®. Para comparar variables cualitativas se obtuvieron la frecuencia y el porcentaje de casos, realizando la prueba del chi cuadrado o el test de Fisher. Las medias entre dos grupos se compararon empleando el test de la "t" de Student. Se consideró estadísticamente significativo un valor de p menor de 0,05. Para el análisis principal de no inferioridad de la variable principal se aplicaron los test de Farrington-Manning, Miettinen-Nurminen y Gart-Nam. Resultados: se incluyeron 73 pacientes, de los cuales 37 recibieron Clinoleic® y 36 SMOFlipid®. En la variable "disminución de infecciones nosocomiales", SMOFlipid® demostró no ser inferior a Clinoleic®. En la variable principal "mortalidad", SMOFlipid® demostró no ser inferior a Clinoleic®. Tampoco existieron diferencias estadísticamente significativas en cuanto a la aparición de efectos adversos. Conclusiones: en nuestro estudio, SMOFlipid® demostró no ser inferior a Clinoleic® en términos de eficacia y seguridad.

[Neonates treated with individualized parenteral nutrition who are candidates to receive standardized parenteral nutrition]. / Neonatos en tratamiento con nutriciones parenterales individualizadas, candidatos a recibir nutriciones parenterales estandarizadas.

INTRODUCTION: Objetive: to quantify the number of neonates treated with individualized parenteral nutrition (IPN) who were candidates to receive standardized parenteral nutrition (SPN), and to calculate their treatment duration. Material and methods: this was a prospective, observational, descriptive cohort study. Inclusion criteria were: neonates with indication of parenteral nutrition (PN) and individualized prescription. Exclusion criteria included: patients who had not started diuresis, with specific nutritional needs, altered acid-base balance, and/or contraindication to receive SPN. Included variables were patient-related (gender, weight, weeks of gestation, and days of life) and treatment-related regarding IPN composition. Setting the volume of PN as the conversion criterion, theoretical contributions were calculated with the SPN. The criterion for a patient to be a candidate to receive SPN was that all the theoretical contributions calculated were within the reference requirements range. Results: a total of 33 neonates (9 women) received IPN with 94 prescriptions. The median weight of the patients included in the study was 2.14 (IQR, 0.9) kg, and they were born at 35 (IQR, 3) weeks of gestation. PN began between 0 and 4 days of life. In all, 71 % (22/31) of the patients in 54.1 % of their (46/85) prescriptions were candidates to receive SPN via central administration for 1 to 8 days, whereas no patient was candidate to receive SPN via peripheral administration. Conclusions: in our center, 71 % of neonates treated with central administration of IPN are candidates to receive SPN, thus promoting the normalization of nutritional support in this population.

INTRODUCCIÓN: Objetivo: cuantificar el número de pacientes neonatos en tratamiento con nutriciones parenterales individualizadas (NPI), candidatos a recibir nutriciones parenterales estandarizadas (NPE), así como el número de días. Material y métodos: estudio prospectivo observacional y descriptivo de cohortes. Los criterios de inclusión fueron: pacientes neonatos con indicación de nutrición parenteral (NP) y prescripción individualizada. Los criterios de exclusión fueron: pacientes que no hubieran iniciado la diuresis, con necesidades nutricionales específicas, con alteraciones del equilibrio ácido-base y/o con contraindicación de la NPE. Se emplearon variables relacionadas con el paciente (sexo, peso, semanas de gestación y días de vida) y relacionadas con el tratamiento (aportes de la NPI). Fijando como criterio de conversión el volumen de NP, se calcularon los aportes teóricos con la NPE. El criterio para que un paciente fuera candidato a recibirla fue que todos los aportes teóricos estuvieran dentro de los requerimientos de referencia. Resultados: se incluyeron 33 neonatos (9 mujeres) en tratamiento con NPI y con 94 prescripciones. La mediana de peso de los pacientes incluidos en el estudio fue de 2,14 (RIC: 0,9) kg, nacidos a las 35 (RIC: 3) semanas de gestación y en los que se inició NP entre los días 0 y 4. El 71 % (22/31) de los pacientes en el 54,1 % (46/85) de sus prescripciones fueron candidatos a recibir NPE administrada por vía central durante 1 a 8 días, mientras que ningún paciente fue candidato a recibirla por vía periférica. Conclusiones: en nuestro centro, el 71 % de los pacientes nenonatos en tratamiento con NPI administrada por vía central son candidatos a recibir NPE, lo que fomenta la normalización del soporte nutricional en esta población.

Stability of N-Acetylcysteine (NAC) in Standardized Pediatric Parenteral Nutrition and Evaluation of N,N-Diacetylcystine (DAC) Formation.

The ESPGHAN/ESPEN/ESPR-Guidelines on pediatric parenteral nutrition (PPN) recommend the administration of the semiessential amino acid (AA) cysteine to preterm neonates due to their biochemical immaturity resulting in an inability to sufficiently synthetize endogenous cysteine. The soluble precursor N-acetylcysteine (NAC) is easily converted into bioavailable cysteine. Its dimer N,N-diacetylcystine (DAC) is almost unconvertable to cysteine when given intravenously resulting in a diminished bioavailability of cysteine. This study aims to understand the triggers and oxidation process of NAC to DAC to evaluate possibilities of reducing DAC formation in standardized PPN. Therefore, different air volumes (21% O2) were injected into the AA compartment of a standardized dual-chamber PPN. O2 concentrations were measured in the AA solution and the headspaces of the primary and secondary packaging. NAC and DAC concentrations were analyzed simultaneously. The analysis showed that O2 is principally delivered from the primary headspace. NAC oxidation exclusively delivers DAC, depending on the O2 amount in the solution and the headspaces. The reaction of NAC to DAC being containable by limiting the O2 concentration, the primary headspace must be minimized during manufacturing, and oxygen absorbers must be added into the secondary packaging for a long-term storage of semipermeable containers.

Use of sodium glycerophosphate in neonatal parenteral nutrition solutions to increase calcium and phosphate compatibility for preterm infants.

BACKGROUND: Preterm infants require higher calcium and phosphate intake than term infants to facilitate adequate bone growth, but this is rarely met in parenteral nutrition (PN) solution because of the limited solubility of calcium and phosphate. This study aimed to evaluate the solubility of organic phosphate with calcium gluconate in neonatal PN solutions, simulating its clinical use. METHODS: PN solutions were composed of calcium gluconate at 50 mEq/L and sodium glycerophosphate (NaGP) at 25 mmol/L. Another component included 1% or 4% amino acid and 10% or 20% dextrose. For comparison, PN solution composed of potassium phosphate was also evaluated. Each solution was evaluated using the following methods: visual inspection, light obscuration particle count test, and pH measurement. To simulate the clinical condition, the solution was tested after compounding, after being stored at 25 °C for 24 h, and after being stored at 2°C-8°C for 2 or 9 days and subsequently at 25 °C for 24 h. RESULTS: There was no visual deposition in PN solution using NaGP in any of the concentrations and under any stored condition. The solution fulfilled the criteria of physical compatibility as < 25 particles/mL measuring ≥10 µm in diameter and <3 particles/mL measuring ≥25 µm in diameter. On the contrary, visual deposition was evidently noted in PN solution using potassium phosphate after its formulation, and the particle count significantly exceeded the range of physical compatibility. CONCLUSION: NaGP and calcium gluconate have significantly good compatibility in PN solution. The use of NaGP in neonatal PN prevents calcium and phosphorus precipitation, hence increasing their supply to preterm infants in meeting their growth requirement.

Phytosterolaemia associated with parenteral nutrition administration in adult patients.

Vegetable lipid emulsions (LE) contain non-declared phytosterols (PS). We aimed to determine PS content depending on the brand and LE batch, and in adult hospitalised patients treated with parenteral nutrition (PN), to establish the association between plasma and administered PS. Part I was the LE study: totals and fractions of PS in three to four non-consecutive batches from six LE were analysed. Part II was the patient study: patients with at least 7 previous days of PN with 0·8 g/kg per d of an olive/soyabean (O/S) LE were randomised (day 0) 1:1 to O/S or 100 % fish oil (FO) at a dose of 0·4 g/kg per d for 7 d (day 7). Plasma PS, its fractions, total cholesterol on days 0 and 7, their clearance and their association with PS administered by LE were studied. In part I, LE study: differences were found in the total PS, their fractions and cholesterol among different LE brands and batches. Exclusive soyabean LE had the highest content of PS (422·36 (sd 130·46) µg/ml). In part II, patient study: nineteen patients were included. In the O/S group, PS levels were maintained (1·11 (sd 6·98) µg/ml) from day 0 to 7, while in the FO group, significant decreases were seen in total PS (-6·21 (sd 4·73) µg/ml) and their fractions, except for campesterol and stigmasterol. Plasma PS on day 7 were significantly associated with PS administered (R2 0·443). PS content in different LE brands had great variability. PS administered during PN resulted in accumulation and could be prevented with the exclusive administration of FO LE.

Physicochemical Compatibility of Dexmedetomidine With Parenteral Nutrition.

BACKGROUND: Dexmedetomidine is an α2-agonist used as a sedative agent in the intensive care setting. Simultaneous administration of dexmedetomidine and parenteral nutrition (PN) may be required. The aim of this study was to evaluate the physicochemical compatibility of dexmedetomidine Y-site administered with PN. METHODS: Three PN and 3 dexmedetomidine solutions were compounded. The tested infusion rate for PN was 66 mL/h. For dexmedetomidine, we considered the initial and maximum infusion rates (0.7 and 1.4 µg/kg/h) detailed in the data sheet. Taking this into account and considering a weight range of 55-95 kg, we tested 2 dexmedetomidine infusion rates (10 and 36 mL/h). The samples obtained were examined visually against light. pH was analyzed with a pH meter. Mean fat droplet diameter was determined by dynamic light scattering. Quantification of dexmedetomidine concentration was carried out by ultraperformance liquid chromatography-high-resolution mass spectrometry. For each PN-dexmedetomidine admixture, tests were performed in triplicate. RESULTS: No alterations were observed by visual inspection. Average pH was 6.25 ± 0.01. Droplet diameter remained below 500 nm (298 ± 10 nm for 10-mL/h rate and 303 ± 5 nm for 36-mL/h rate). Dexmedetomidine concentrations at t = 0 were 519 ± 31 ng/mL and 1391 ± 90 ng/mL for 10- and 36-mL/h infusion rates, respectively. At t = 24 hours, the concentrations obtained were 494 ± 22 and 1332 ± 102 ng/mL, which translates into ≥90% of the initial concentrations. CONCLUSION: Dexmedetomidine is physicochemically compatible with PN during simulated Y-site administration at the tested infusion rates.

Investigation of tryptophan-related yellowing in parenteral amino acid solution: Development of a stability-indicating method and assessment of degradation products in pharmaceutical formulations.

Parenteral amino acid solutions containing tryptophan tend to develop a yellow colouration upon storage. Hence, the aim of the present study was to find out whether tryptophan degradation products are the reason for the yellowing. The degree of discolouration and tryptophan degradation was examined by visual examination and UV/Vis measurements with respect to oxygen presence, pH value, and duration of steam sterilization. LC-UV analyses of autoclaved tryptophan solutions indicated eight degradation products, namely R,R/R,S 2-amino-3-(oxoindolin-3-yl)propanoic acid, R,R/R,S 2-amino-3-hydroxy-2-oxoindolin-3-yl)propanoic acids, cis/trans 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid, N´-formylkynurenine, and kynurenine. The proposed degradation products were confirmed by spiking of synthesized degradation products and LC-UV/MS analyses. The LC-UV analysis method was optimized and validated according to the ICH guideline Q2 (R1). Tryptophan stability in commercially available parenteral amino acid formulations was evaluated over a storing period of 12 months in two common types of primary packaging after autoclave procedure.

In vitro compatibility studies of vancomycin with ready-to-use parenteral nutrition admixtures for safer clinical practice.

BACKGROUND & AIMS: A co-infusion of parenteral nutrition (PN) and other drugs is often necessary in patients with a limited number of vascular access sites. This practice increases the risk of interaction between drugs and PN admixtures that may be manifested as drug precipitation or lipid emulsion destabilization. The present study aimed to determine the compatibility between vancomycin (VMC) and five ready-to-use PN admixtures utilized worldwide (Kabiven, Nutriflex Lipid Special, Olimel N9E, Nutriflex Omega Special, and Smofkabiven) in order to assess the possibility of their co-administration via Y-sites. METHODS: VMC and PN admixtures were mixed at three volume ratios (1:1, 1.5:1, and 3:1) and potential interactions were examined using visual inspection, pH and osmolality measurements, as well as particle size and zeta potential determination. The analyses were conducted immediately after sample preparation and after 4 h of storage. RESULTS: The PN admixtures were characterized by the pH in the range from 5.44 to 6.23, the osmolality in the range from 1169 ± 3 mOsm/kg H2O to 1929 ± 6 mOsm/kg H2O. The zeta potential of the PN admixtures was between -12.97 ± 0.86 mV and -4.55 ± 0.45 mV. The particle size, expressed as mean droplet diameter (MDD) ranged from 226.8 ± 4.2 nm to 281.6 ± 6.3 nm. The addition of VMC to PN admixtures caused a decrease in the pH, osmolality, and zeta potential. The MDD values for all samples were below 500 nm, except VMC-Olimel N9E at the volume ratio 1:1 (v/v), for which MDD = 805 nm. The presence of lipid particles exceeded the size of 4000 nm was observed for VMC-Olimel N9E and VMC-Smofkabiven. CONCLUSIONS: We suggest that a simultaneous administration of VMC with PN admixtures containing olive oil should be avoided. As we established, this type of emulsion is less stable and tends to form agglomerates when combined with VMC. However, as demonstrated in our study, when it is necessary to co-administer VMC with PN admixtures, this is possible with Kabiven, Nutriflex Lipid Special, and Nutriflex Omega Special at volume ratios of 1:1, 1.5:1, and 3:1.

Low caloric intake and high fluid intake during the first week of life are associated with the severity of bronchopulmonary dysplasia in extremely low birth weight infants.

OBJECTIVE: To study whether there is an association between nutritional intake during the first week of life and severity of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. METHODS: In a retrospective cohort study, medical records of all ELBW infants admitted to our Neonatal Intensive Care Unit (2010-2017) were reviewed for infants' demographics, clinical characteristics, nutritional intake during their first week of life, and BPD risk factors. RESULTS: During the study period 226 infants were identified of whom 67% (151/226) had moderate-severe BPD and the rest served as controls. Overall infants with moderate-severe BPD were younger, smaller, and spent more time on mechanical ventilation than their controls [(mean±standard deviation) 24.7±1.7 vs. 26.8±2.0 weeks gestational age (p < 0.001); 678±154 vs. 837±129 grams (p < 0.001); and 37.9±23.6 vs. 13.7±15.3 days (p < 0.001) respectively]. During the first week of life, the average caloric, carbohydrate, protein and lipid intakes were significantly lower, and the average fluid intake was significantly higher in the moderate-severe BPD than the control group. After adjustment for confounders, fluid intake, and days on mechanical ventilation were significantly associated with moderate-severe BPD with an odds ratio [OR (95% confidence interval)] of 1.03 (1.01-1.04), and 1.05 (1.03-1.07) respectively. Daily caloric intake was associated with an increased risk for moderate-severe BPD [OR: 0.94 (0.91-0.97)]. CONCLUSION: Low caloric intake, and high fluid intake during the first week of life are associated with the severity of BPD in ELBW infants.

Stability of high-dose thiamine in parenteral nutrition for treatment of patients with Wernicke's encephalopathy.

BACKGROUND & AIMS: Wernicke's encephalopathy is associated mainly with malnourishment in alcohol-dependent patients but can be caused also by cancer, Crohn's disease, gastrointestinal surgery or prolonged parenteral nutrition (PN) without adequate supplementation of vitamins. The disorder, with a significant mortality rate of up to 20%, is often associated with the underlying disease and intensifies after administration of non-supplemented PN. Thus, it seems justified to add thiamine to PN admixtures prepared for parenterally fed patients. Due to the lack of data on the stability of thiamine in PN admixtures at concentrations exceeding 60 mg/L, we decided to determine the possibility of adding a high dose of thiamine (800 mg per bag, 320 mg/L) to PN admixtures in order to treat Wernicke's encephalopathy in malnourished patients. METHODS: The study aimed to assess the stability of the physical properties of PN admixtures (pH, zeta potential, particle size) and to determine thiamine content using an HPLC method. RESULTS: Thiamine was found to degrade regardless of the PN admixture composition and storage conditions. The highest decrease in thiamine content was observed at room temperature without light protection whereas the lowest at a temperature of 4 ± 1 °C with light protection. CONCLUSIONS: The treatment of Wernicke's encephalopathy in parenterally fed patients is possible with the use of high thiamine doses (800 mg) added to PN admixtures without a decrease in the drug content above 10% within the first 24 h. It should be emphasized that thiamine as a photosensitive drug must be stored and administered under conditions ensuring light protection.

All-in-one versus lipid-free parenteral nutrition for premature infants: visual, pH, and particle size analyses / Comparación de nutrición parenteral "todo-en-uno" frente a nutrición parenteral sin lípidos en prematuros: análisis visual, de pH y tamaño de partículas

Objective: this study aims to investigate the physical stability of standard formulations for parenteral nutrition, with and without lipids, in one bag for preterm babies. Method: standard formulations for first-day and for second-day parenteral nutrition of preterm babies weighing 1,000 grams were prepared in triplicate. Standard all-in-one formulas for first-day and for second-day parenteral nutrition were compared with equivalent standard lipid-free formulations. The standard formulas contain glucose, amino acids, lipids, calcium gluconate, potassium chloride, sodium chloride, and vitamins. Stability was evaluated using visual inspection, particle size analysis, and pH measurement. The physical instability of the all-in one parenteral nutrition formulas was reported as creaming, coalescence, or cracking, whereas the instability of the lipid-free parenteral nutrition formulas was described as turbidity, precipitation, gas formation, or colour changes. Two independent evaluators assessed the visual changes under light and against a dark-light background, as well as using the Tyndall beam effect. Particle size was measured using a particle size analyzer. Chemical compatibility was checked using a pH-meter. Result: the result showed that the all-in-one (AIO) parenteral nutrition formulas develop reversible creaming on day three, while the lipid-free ones remain clear. As regards pH and particle size, none of the four AIO and lipid-free formulas developed significant changes (?pH < 0.05 and particle size < 400 nm) until after seven days

Objetivo: el objetivo del estudio es investigar la estabilidad de las formulaciones estandarizadas de nutrición parenteral, con y sin lípidos, para prematuros. Métodos: se prepararon por triplicado las formulaciones estandarizadas del 1º y 2º día para prematuros de menos de 1000 gramos. Se compararon las soluciones preparadas "todo-en-uno" con las soluciones estandarizadas equivalentes que no contenían lípidos. Las soluciones estandarizadas contenían glucosa, aminoácidos, lípidos, gluconato cálcico, cloruro potásico, cloruro sódico y vitaminas. La estabilidad se evaluó mediante inspección visual, medición del tamaño de las partículas, y medición del pH. Se interpretó como inestabilidad física de las soluciones ternarias la presencia de separación de fases, coalescencia o la formación de una capa grasa, mientras que en las preparaciones sin lípidos se describió como turbidez, precipitación, formación de gas o cambios de coloración. Dos evaluadores independientes comprobaron los cambios visuales bajo luz directa o en contraste con un fondo oscuro, así como mediante el uso del efecto Tyndall. El tamaño de las partículas se midió mediante un analizador de partículas. La compatibilidad química se comprobó con el Phmetro. Resultados: todas las nutriciones parenterales todo-en-uno (AIO) desarrollaron una capa grasa (creaming) al tercer día, mientras que las mezclas sin lípidos permanecieron transparentes. Con respecto al pH y el tamaño de las partículas, ninguna de las cuatro emulsiones AIO y nutrición parenteral sin lípidos mostraron cambios significativos (incremento de pH < 0,03 y tamaño de las partículas < 400 nm) en los siete primeros días