Compatibility and stability of additives in parenteral nutrition admixtures

doi:10.1016/S0899-9007(98)00063-X

Nutrition

Volume 14, Issue 9, September 1998, Pages 697-706

https://doi.org/10.1016/S0899-9007(98)00063-X Get rights and content

Abstract

The addition of additives (electrolytes, trace elements, and vitamins) to parenteral nutrition (PN) mixtures can lead to precipitation as a result of physical incompatibilities and can lead to chemical degradation of individual ingredients. The most significant cause of precipitation is excessive concentrations of calcium phosphate. The most significant cause of chemical instability is the oxidation of specific vitamins. The factors influencing calcium phosphate solubility include the commercial amino acid source, the calcium and phosphate salts used, temperature, magnesium concentration, and final volume. Precipitation can be avoided by organic phosphates. Trace element precipitation is most commonly caused by the formation of iron phosphate salts or copper cysteinate in cysteine-containing amino acid infusions. The least stable nutrient is ascorbic acid, which reacts with oxygen, and is catalyzed by copper ions. Oxygen originates from PN ingredients, the filling process, air remaining in the bag after filling, and oxygen permeation through the bag wall. Storage in multilayered bags with reduced gas permeability can protect residual ascorbic acid. Other chemical losses are caused by the reduction of thiamine by metabisulfite, and photodegradation of daylight-sensitive vitamins, especially retinol and riboflavin, during administration.

Introduction

The compounding of parenteral nutrition (PN) admixtures in large volume plastic containers (“big bags”) leads inevitably to infusions that are less stable than the constituent components. The individual injections used in the compounding of any mixture are manufactured as relatively stable products with shelf-lives measured in years. Stability is maintained by optimizing both the formulation and packaging of the products. Once each injection or infusion has been removed from its original container and mixed with other parenteral ingredients, the chemical stability of the active ingredients and also any excipients will be compromised. In addition, the mixing of various compounds may lead to loss of physical compatibility by formation of new salts of low aqueous solubility compared with constituent chemical components, leading to precipitation.

It is the purpose of this review to consider the possible causes for chemical degradation and physical incompatibility in PN admixtures that involve parenteral additives, and to relate the significance of these changes to clinical consequences.

For the purpose of this review, the parenteral additives reviewed include electrolytes, trace elements, and vitamins. Mechanisms to avoid these unfavorable reactions are considered.

Section snippets

Electrolytes

All PN regimens must contain a range of essential electrolytes, some of which must be included within a particular concentration range (for example potassium and sodium coincident with the clinical condition of the patient), whereas others must be present in amounts at least sufficient to provide a minimum daily requirement (for example calcium, magnesium, and phosphate). Individual patient requirements depend on a number of factors, such as clinical condition, age, renal function, and their

Trace element incompatibility

A wide range of trace elements are necessary to meet the nutritional needs of patients receiving PN. The list of recognized requirements has grown with our increasing knowledge of micronutrient functions in nutrition. The list includes such elements as selenium, molybdenum, chromium, and bromine, as well as the more obvious iodine, fluorine, manganese, and copper. Daily requirements remain, in many cases, poorly defined, although both the minimum and maximum amounts are defined for most

Summary of physical incompatibility

The risk of calcium phosphate precipitation is the major problem regarding the addition of electrolytes and trace elements to PN mixtures. The mechanisms and consequences are now well recognized. Clear strategies are available to avoid this physical incompatibility. The most promising development is the availability of organic phosphate injections that provide a means of avoiding any risk associated with calcium phosphate precipitation. Our limited knowledge of trace element stability in PN

Vitamin stability

Vitamins are commonly believed to be among the least stable ingredients in PN mixtures, and it is generally recommended that vitamins be added immediately before commencing infusion or that infusion should be commenced within 24–48 h of addition. This constraint poses severe limitations on the ability of compounding units to provide aseptically prepared complete PN mixtures. A careful consideration of the stability of vitamins is crucial to the operation of safe and effective compounding

Retinol

Multivitamin additives intended for PN may contain either the acetate or palmitate ester of retinol. The former compound is commonly used in formulations originating from the USA.

The stability of retinol in PN mixtures during storage has been widely reported. Allwood35 has shown that retinol (palmitate) is stable in two-in-one mixtures for at least 28 d during storage at 5°C. Billion-Rey et al.37 reported that retinol (palmitate) was stable for 20 d in all-in-one PN mixtures stored at 4°C,

Riboflavin

Riboflavin has been reported to be stable for at least 4 d in all-in-one PN mixtures stored at 2–8°C,35 and for 48 h at 5°C or ambient temperature in a range of PN mixtures.54 Kearney et al.54 reported that riboflavin is relatively stable (> 80% remaining) after 8 wk of storage at 5°C in two-in-one PN mixtures containing different amino acid infusions.

Riboflavin is degraded by exposure to daylight,56 although it is less sensitive than retinol. Chen et al.56 reported total degradation of

Summary

Common practice is to avoid adding vitamins to PN mixtures until immediately before administration, in which case the addition is commonly made by ward staff at the bedside, without pharmaceutic control. The least stable vitamin is undoubtedly ascorbic acid, and losses during administration can be substantial, although these can, to some extent, be predicted by our knowledge of the mechanisms involved in ascorbate oxidation. Because degradation is directly related to oxygen content of

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Stability and compatibility of parenteral nutrition solutions; a review of influencing factors
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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.
Stability of high-dose thiamine in parenteral nutrition for treatment of patients with Wernicke's encephalopathy
2020, Clinical Nutrition
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.
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.
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.
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.
Implementation of a tool for Y-site drug interaction detection: Retrospective analysis of prescriptions in a hematology unit
2019, Pharmacien Hospitalier et Clinicien
Chez le patient recevant des perfusions complexes, la connaissance et la gestion des incompatibilités physico-chimiques sont essentielles. Les objectifs de cette étude sont en premier lieu la mise au point d’un outil simple permettant la détection de ces incompatibilités et ensuite l’évaluation de l’intérêt pratique de cet outil dans le cadre d’une analyse rétrospective des prescriptions des patients hospitalisés en hématologie. Enfin l’étape finale est l’utilisation de cet outil en vie réelle afin de sécuriser les prescriptions.
L’analyse des consommations du service, nous a permis d’établir une liste exhaustive des substances actives (SA), des solvants et de la nutrition parentérale les plus prescrits. A partir de cette liste nous avons construit un outil répertoriant les niveaux d’interactions en Y (à type de compatibilité, d’incompatibilité, de compatibilité variable) et ce pour chaque couple de SA. Nous avons étudié et analysé 680 prescriptions émises pendant une période d’une année, parmi lesquelles 430 comportaient plus de 2 injectables différents, pour un total de 15 177 couples d’interactions possibles.
L’étude rétrospective menée retrouve : 22,3 % couples compatibles, 7,0 % incompatibles, 0,4 % avec une compatibilité variable. Par ailleurs notre étude a montré que pour 70,3 %, la compatibilité n’est pas décrite. Nous avons mis en évidence que le nombre d’incompatibilités est proportionnel au nombre d’injectables prescrit et devient supérieur à 1 dès 7 injectables coprescrits.
L’élaboration et l’utilisation de cet outil interactif, simple et pratique permet lors de l’analyse pharmaceutique, en complément de l’analyse de niveau 3 (selon la SFPC) : analyse des données biologiques du patient, des interactions PK/PD ; de détecter les interactions liées à la co-administration des médicaments injectables en Y.
In patients receiving complex infusions, knowledge and management of physical and chemical incompatibilities are essential. The aims of the present study were to develop a simple tool to help detect such incompatibilities and to assess its practical interest in a retrospective analysis of prescriptions for hematology department patients. The final step is real-life application to secure the prescription pathway.
Analysis of hematology department drug consumption established an exhaustive inventory of the most frequently prescribed active substances, solvents and parenteral nutrients. Based on this, we built a tool listing pair-wise Y-site interactions one 3 levels: compatibility, incompatibility, variable compatibility. For a 1-year period, 680 prescriptions were analyzed, 430 of which comprised more than 2 intravenous drugs: i.e., 15,177 possible interaction pairs.
On retrospective analysis, 22.3 % of these were compatible, 7.0 % incompatible, 0.4 % had variable compatibility and in 70.3 % compatibility was not reported. The number of incompatibilities was proportional to the number of substances prescribed, becoming greater than 1 when ≥ 7 substances were prescribed.
The development and implementation of this simple and practical interactive tool enables level III analysis of patient biological data and PK/PD-based drug-drug interactions according to the French Society of Clinical Pharmacology (SFPC) to be supplemented by pharmaceutic detection of interactions related to Y-site co-administration of intravenous drugs.
Do carnitine and extra trace elements change stability of paediatric parenteral nutrition admixtures?
2019, Clinical Nutrition
High concentrations of trace elements (TE), in particular zinc and selenium, along with carnitine, are often added to parenteral admixtures in paediatric patients on long-term Parenteral Nutrition (PN). We aim to evaluate whether lipid droplet diameters of these admixtures maintain the recommended range of 0.4–1.0 μm.
Stability studies were carried out on six parenteral admixtures with carnitine, trace elements and electrolytes added in different amounts. Each admixture was formulated with five different lipid emulsions with or without fish oil. Analyses were performed at time 0 (t = 0) and 24, 48, 72, 96 (t = 96) hours after compounding. Droplet diameters were determined by Light Scattering-Reverse Fourier Optics Technique. Samples, stored at 4 °C, were triple tested for a total of 450 analyses. Regression analyses were performed using panel-data techniques.
During the 4 days, lipid droplet diameters were in the expected range of 0.4–1.0 μm regardless of trace element and carnitine amounts in all admixtures apart from those containing fish-oil based emulsions and calcium concentrations equal to 4.5 mmol/L. In these latter admixtures, 12% of droplet diameters were larger than 1.0 μm and 2% exceeded 5.0 μm immediately after compounding.
Carnitine and high concentrations of trace elements do not affect PN admixtures stability and can be safely infused in long-term home-PN paediatric patients and prematures. Only high calcium concentrations in compresence with fish oil based lipid emulsions seem to change PN stability.
Assessment of paediatric parenteral nutrition administration practices: Observational audit and self-evaluation in a French University Hospital
2018, Nutrition Clinique et Metabolisme
L’administration de la nutrition parentérale (NP) est une pratique à risque. Suite à l’instruction de la direction générale de l’offre de soins (DGOS) du 20 mars 2015, un audit observationnel et une autoévaluation des pratiques d’administration de la NP pédiatrique étaient réalisés. L’objectif de ce travail était de mesurer les écarts entre la pratique observée ou déclarée et celle attendue au regard des référentiels existants.
Un audit observationnel, selon une grille composée de 19 critères issus des recommandations de l’inspection générale des affaires sociales (IGAS), de la haute autorité de santé (HAS) et de la DGOS, puis un questionnaire d’autoévaluation destiné aux infirmières de pédiatrie étaient réalisés.
Lors du branchement de la poche, une friction hydro-alcoolique des mains était réalisée dans plus de 90 % des cas. Les contrôles préalables à l’administration étaient globalement respectés (> 80 %). Concernant l’administration, la pose d’un filtre sur la ligne de perfusion était effective dans 41 % des cas (60 % pour l’autoévaluation). Trois changements de ligne de perfusion étaient non conformes (8,6 %). Seulement 6 % des infirmières diplômées d’état déclaraient avoir reçu une formation spécifique.
Cette étude permettait de dresser un état des lieux des connaissances et des pratiques professionnelles relatives à l’administration de la NP pédiatrique, quel que soit le type de poches. Si certains critères spécifiés par l’instruction de la DGOS étaient respectés, les connaissances et les pratiques des IDE étaient hétérogènes sur d’autres points, nécessitant la mise en place d’actions d’amélioration.
The administration of parenteral nutrition is a high-risk practice. Following the French instruction (direction générale de l’offre de soins [DGOS]) of March 20, 2015, an observational audit and a self-evaluation of pediatric parenteral nutrition administration practices were performed. The objective of this study was to compare the observed or declared practices with present recommendations.
An observational audit was performed, with a grid composed of 19 criteria according to the French recommendations (inspection générale des affaires sociales [IGAS], Haute Autorité de santé [HAS] and the DGOS), then with a questionnaire of self-evaluation for nurses in pediatric unit.
When connecting the bag, a hydro-alcoholic friction of the hands was achieved in more than 90% of cases. Controls before administration were respected (more than 80%). Regarding administration, the positioning of a filter on the line was effective in 41% of cases (60% for self evaluation). Three administration line changes were observed as non-compliant (8.6%). Only 6% of nurses reported having received specific training.
This survey showed the knowledge and professional practices concerning the administration of pediatric parenteral nutrition, whatever the kind of bag. If some criteria specified by the DGOS instruction were respected, the nurse's knowledge and practices were heterogeneous on other points, requiring the implementation of improvement measures.
Safety in parenteral nutrition compounding
2023, Nutrition in Clinical Practice

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Review ArticlesCompatibility and stability of additives in parenteral nutrition admixtures

Abstract

Introduction

Section snippets

Electrolytes

Trace element incompatibility

Summary of physical incompatibility

Vitamin stability

Retinol

Riboflavin

Summary

The solubility of calcium and phosphorus in neonatal total parenteral nutrition solutions

JPEN

Compatibility of calcium chloride and calcium gluconate with sodium phosphate in a mixed TPN solution

Am J Hosp Pharm

Calcium and phosphorus in neonatal parenteral nutrition solutions

JPEN

Compatibility and stability of electrolytes, vitamins and antibiotics in combination with 8% amino acid solution

Am J Hosp Pharm

Precipitation of calcium phosphate from parenteral nutrient fluids

Am J Hosp Pharm

The compatibility of calcium phosphate in paediatric TPN infusions

J Clin Pharm Ther

Calcium and phosphate solutions in neonatal parenteral nutrient solutions containing Aminosyn-PF or Trophamine

Am J Hosp Pharm

Calcium and phosphorus compatibility in parenteral nutrition solutions for neonates

Am J Hosp Pharm

Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions

N Engl J Med

Calcium and phosphate solubility in neonatal parenteral nutrient solutions containing aminosyn PF

Am J Hosp Pharm

Electrolyte compatibility in a synthetic amino acid hyperalimantation solution

Am J Hosp Pharm

Aporte de glucosa-l-fosfato en nutricion parenteral total protocolizada

Nutr Hosp

Stability of parenteral nutrition admixtures containing organic phosphates

Clin Nutr

Efficacy of calcium glycerophosphate vs conventional mineral salts for total parenteral nutrition in low-birth-weight infantsa randomized clinical trial

Am J Clin Nutr

Safety alerthazards of precipitation associated with parenteral nutrition

Am J Hosp Pharm

Assessment of trace element compatibility in total parenteral nutrition infusions

Pharm Weekbl (Sci)

Stability of total parenteral nutrition supplied as “all-in-one” for children with chemotherapy-linked hyperhydration

Pharm Weekbl (Sci)

Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition

JPEN

Precipitate analysis from an in-dwelling total parenteral nutrition catheter

JPEN

The availability of trace elements in intravenous hyperalimentation solutions

Drug Intell Clin Pharm

Trace element formulations in intravenous feeding

Intravenous solution compatibility and filter-retention characteristics of trace element preparations

Am J Hosp Pharm

The compatibility of four trace elements in total parenteral nutrition infusions

Int J Pharmaceutics

Precipitate in admixtures of new amino acid injection

Am J Hosp Pharm

Precipitate in admixtures of new amino acid injection, reply

Am J Hosp Pharm

Dilute iron dextran formulation for addition to parenteral nutrient solutions

Am J Hosp Pharm

Supplementation of total parenteral nitrition solutions with ferrous citrate

JPEN

Considerations in the design of selenium bioavailability studies

Fed Proc

Selenium stability in TPN solutions

Am J Clin Nutr

Selenium and vitamin E stability on parenteral solutions

JPEN

Chemical stability of selenious acid in total parenteral nutrition solutions containing ascorbic acid

JPEN

The wavelength-dependent degradation of vitamin A exposed to ultraviolet light

Int J Pharmaceutics

Vitamin stability in a TPN mixture stored in an EVA plastic bag

J Clin Hosp Pharm

Stability of vitamins in TPN solutions stored in 3 litre bags

Brit J Intraven Ther

Stability of fat-soluble vitamins A (retinol palmitate), E (tocopherol acetate) and K1 (phylloquinone) in total parenteral nutrition at home

JPEN

Review Articles
Compatibility and stability of additives in parenteral nutrition admixtures