Compatibility of medications with 3-in-1 parenteral nutrition admixtures

BACKGROUND: The absence of drug compatibility information with 3-in-1 parenteral nutrition admixtures has been problematic. The purpose of this project was to evaluate the physical compatibility of 106 selected drugs during simulated Y-site injection into nine different 3-in-1 parenteral nutrition admixture formulations. METHODS: Four-milliliter samples of each of the representative 3-in-1 parenteral nutrition admixture formulations were combined in a 1:1 ratio with 4-mL samples of each of 106 drugs, including supportive care drugs, anti-infectives, and antineoplastic drugs. Six replicate samples of each combination were prepared. Two samples were evaluated initially after mixing, two more after 1 hour, and the last two after 4 hours at 23 degrees C. At each test interval, the samples were subjected to centrifugation, causing the fat to rise to the top. The top fat layer and most of the aqueous phase were removed, and the remaining liquid was diluted with about 7 mL of particle-free, high-performance liquid chromatography-grade water to facilitate observation of any particulates that might have formed. Visual examinations were performed in normal diffuse fluorescent laboratory light and under high-intensity, monodirectional light. RESULTS: Most of the drugs tested were physically compatible with the 3-in-1 parenteral nutrition admixtures for 4 hours at 23 degrees C. However, 23 drugs exhibited various incompatibilities with one or more of the parenteral nutrition admixtures. Six drugs resulted in the formation of precipitate with some or all of the admixtures. Seventeen drugs caused disruption of the emulsion, usually with oiling out. CONCLUSIONS: Most of the test drugs were physically compatible with the nine representative 3-in-1 parenteral nutrition admixtures. However, the 23 drugs that resulted in incompatibilities should not be administered simultaneously with the incompatible parenteral nutrition admixtures via a Y injection site.     

Practical aspects of multichamber bags for total parenteral nutrition

PURPOSE OF REVIEW: Ready-to-use all-in-one admixtures are standards for short and long-term parenteral nutrition. Their limited stability does not allow storage over prolonged periods of time. Multichamber bags represent industrially manufactured near complete standard parenteral nutrition premixes with extended shelf lives. This review focuses on the characterization of multichamber bags, their influence on parenteral nutrition practice, the need for individual parenteral nutrition compounding, and the role of the pharmacist in the nutrition team. RECENT FINDINGS: The all-in-one admixture concept, its correlation with parenteral nutrition effectiveness, safety, and pharmaceutical issues are reviewed. Multichamber bags, the bag material, their use and practical handling are addressed. SUMMARY: Newly developed container materials are mainly responsible for the increased stability of multichamber bag parenteral nutrition premixes. Multichamber bags are used for (standard) parenteral nutrition in adults. Multichamber bags cannot eliminate individualized all-in-one parenteral nutrition compounding. Pharmaceutical assistance with expertise in compatibility and stability is mandatory for the nutrition team to implement and control good parenteral nutrition practices, e.g. to convert multichamber bags into complete ready-to-use all-in-one admixtures or to compound individualized regimens. The incorporation of additional components into parenteral nutrition admixtures (pharmaconutrients, drugs) must rely on documented compatibility with the parenteral nutrition admixtures. Multichamber bags have their advantages and limitations. Studies on the effectiveness and costs of multichamber bags are needed to meet the expectations of pharmacists, physicians, nurses, and industry for optimal parenteral nutrition in patients.     

Stability and compatibility of histamine H2-receptor antagonists in parenteral nutrition mixtures

PURPOSE OF REVIEW: To examine the stability and compatibility of histamine H2-receptor antagonists in parenteral nutrition admixtures in order to provide well tolerated and effective therapy. RECENT FINDINGS: Many stability investigations were carried out before 2005, but no critical appraisal of published data has been undertaken. H2-receptor antagonists are stable in most parenteral nutrition admixtures for 2-48 h, with long-term stability up to 4 weeks claimed for a few combinations. Some earlier data are questionable in the light of more recent analytical technology and pharmaceutical knowledge regarding stability assessment. As stability is dependent upon the source of constituents, we have listed all products tested and their respective manufacturers. A general recommendation is made not to store H2-receptor antagonists in parenteral nutrition for more than 24 h at refrigerated temperature before use. SUMMARY: Administration of H2-receptor antagonists in parenteral nutrition admixtures has several clinical and economical advantages, but, in order for these benefits to be well tolerated and efficacious, the stability and compatibility of the drugs, as well as the parenteral nutrition components after mixing, have to be ascertained. Factors that influence stability are assessed, the need for more controlled study protocols is evaluated and recommendations are made for safe storage and administration.     

Change in blood vitamin levels in surgical patients given a multivitamin preparation (NK-041) for total parenteral nutrition

We studied the utility of a trial multivitamin preparation 'NK-041' for total parenteral nutrition. This preparation was used in 260 surgical patients during total parenteral nutrition, and changes in their blood vitamin levels were analyzed. Blood levels of all vitamins administered varied within the respective normal ranges, with few exceptional patients. During the administration of NK-041, avitaminosis, hypervitaminosis and side-effects were not observed. Laboratory examinations demonstrated that no abnormalities attributable to this preparation had arisen in these patients. Thus, these results seem to warrant the conclusion that NK-041 is useful as a multivitamin preparation for total parenteral nutrition, with no adverse effects.     

Stabilité galénique de mélanges commercialisés de nutrition parentérale en présence de médicaments. (ii) : médicaments perfusés en Y

The aim of the study was to assess compatibility of 7 commonly used parenteral drugs with 3 commercialized total parenteral admixtures (Kabimix^® 1200, Kabiven^® 1600 and Clinomel^® N7-1000) during simulated Y-site infusion. Parenteral drug (acyclovir, amikacin, heparin, methylprednisolone, ondansetron, ranitidine and vancomycin) were simulated infused during 60 min. Samples were collected at T0 (total parenteral nutrition only), T30min and T60min (simulated Y-site infusion), and T75min (back to parenteral admixtures without drugs). Stability assessment included particle-size analysis, zeta potential measurement, pH determination and visual inspection. Precipitation of acyclovir was found. It depends on acyclovir concentration and on the total parenteral nutrition flow rate. Only maximal flow rate of the parenteral admixture and high drug concentration resulted in acyclovir precipitation. Moreover, precipitation led to a change in particle-size distribution with 3 to 9% of particles greater than 5 μm. The other drugs tested were physically compatible during Y-site infusion with the parenteral admixtures. However, amikacin caused a dramatic increase of the zeta potential which came near the critical emulsion stability zone. This effect must be taken into account in case of parenteral admixtures with initial zeta potential near the critical zone. No difference was found between the 3 commercialized total parenteral admixtures.     

Physicochemical stability of parenteral nutrition supplied as all-in-one for neonates

BACKGROUND: Common clinical practice for the provision of parenteral nutrition of neonates is to administer the nutrients in separate solutions. The aim of this study was to introduce and examine an alternative way of parenteral feeding for neonates, providing all-in-one parenteral regimes. METHODS: Stability studies were carried out on 2 all-in-one admixtures. Stability assays consisted of the assessment of the admixture's (1) macroscopic aspect, (2) drop size measurement, (3) pH measurement, (4) peroxide value, and (5) alpha-tocopherol concentration. For the measurements, the admixtures were stored at 2 different temperatures, 4 degrees C (storage) and 25 degrees C (compounding), and then analyzed at a starting time, 24 hours, 48 hours, and 7 days after compounding. RESULTS: The 2 all-in-one parenteral admixtures for neonates were shown to be physically stable under analysis conditions, and there were no particles larger than 1 mum. The maximum loss of alpha-tocopherol was approximately 24%. In all-in-one admixtures, lipid peroxide occurred within 24 hours after the addition of the lipid emulsion. CONCLUSIONS: The addition of fat emulsion and fat-soluble vitamins did not alter the physical stability of parenteral admixtures for neonates. Moreover, the admixtures examined were relatively chemically stable for 24 hours, as far as vitamin E is concerned. Lipid peroxidation was the limiting factor for application stability of an all-in-one neonatal parenteral regimen.     

Stability of parenteral nutrition admixtures containing organic phosphates

The use of organic phosphates to avoid calcium phosphate precipitation in parenteral nutrition mixtures has been proposed. The purpose of this study was to evaluate the stability of total parenteral nutrition admixtures containing glucose-1-phosphate or glycerol phosphate as the phosphate source over 3 days. Three parenteral nutrition admixtures, each containing glucose-1-phosphate (30.0 mmol), glycerol phosphate (31.4 mmol) or inorganic phosphate (30.0 mmol), and their corresponding aqueous phases were prepared in 3-L ethylene vinyl acetate plastic bags and infusion bottles, and stored at 5 +/- 1 degrees C or 22 +/- 3 degrees C without light protection. Physical stability analysis and sampling for chemical analysis was performed at 0, 24, 48 and 72 h. Aqueous phases were subjected to physical stability analysis, including pH measurement, visual inspection and nephelometry. Admixtures were subjected to physical stability analysis consisting of pH measurement, and evaluation of emulsion stability by visual inspection, degree of creaming, phase contrast microscopy, zone sensing technique and photon correlation spectroscopy. Chemical analyses of amino-acids, dextrose, triglycerides, phospholipids, Na, K, Cl, Mg, Ca, glucose-1-phosphate, glycerolphosphate and inorganic phosphate were performed. No precipitation was detected in any of the aqueous phases. Admixtures remained acceptable with respect to visual and microscopic appearance, mean droplet diameter and droplet size distribution. All nutrient concentrations assayed in the three admixtures remained constant over the study period. Total parenteral nutrition admixtures for adult patients containing glucose-1-phosphate or glycerolphosphate are physically and chemically stable for 3 days when stored under refrigeration or controlled room temperature without light protection.     

Contenants et contaminants en nutrition parentérale : l’aluminium,un revenant ?

Aluminium is a well-known potentially hazardous contaminant in parenteral preparation for dialysis or drug delivery. The main objective of the study is to assess aluminium exposure from chronic parenteral nutrition supply. The specific objectives of the study were (i) to assess aluminium concentration in parenteral nutrition compounds (n = 26) and in hospital-made parenteral nutrition mixture (n = 56), (ii) to compare aluminium concentration in nutrition products to the maximum allowable concentration (i.e. 25 μg/L), and finally (iii) to compare the daily rate infused per kilogram of weight to the limit value recommended by American Society of Parenteral and Enteral Nutrition (i.e. 2 μg.kg^?1 per day). Aluminium content, assessed by atomic absorption spectrophotometry, was determined in parenteral nutrition compounds and in hospital-made parenteral nutrition admixtures to clinically stable patients undergoing total or partial parenteral nutrition. Aluminium concentration in fourteen parenteral nutrition compounds and all parenteral nutrition admixtures excessed 25 μg/L. Furthermore, two thirds of patients were exposed to a rate of aluminium significantly upper than that recommended by the American Society of Parenteral and Enteral Nutrition (i.e. 2 μg.kg^-1 per day). This study shows that parenteral nutrition compounds and parenteral nutrition admixtures were overloaded in aluminium. A monograph specifying acceptable aluminium content of parenteral nutrition products seems necessary for further redaction of European pharmaceutical norm or guidance.     

Effects of pH, temperature, concentration, and time on particle counts in lipid-containing total parenteral nutrition admixtures

It has been standard practice in the United States to separate lipid emulsion from the other components of total parenteral nutrition (TPN) due to the reported instability of admixed intravenous lipid emulsions. Some clinicians, however, have combined all TPN components into one container and administered these admixtures to patients without apparent difficulties. Infusion of all nutrients from one container has many advantages. In this study standard and concentrated admixtures were aseptically prepared using generally accepted guidelines of the nutritional requirements for a 70-kg patient. Treatments of standard and concentrated admixtures consisted of: storing at 4 degrees C without adjusting the pH; increasing the pH to 6.6 and storing at 4 degrees C; increasing the pH to 6.6 and storing at room temperature. Samples were monitored for 3 weeks by means of Coulter Counter analysis, pH determinations, and visual observations. The pH of the admixtures did not change over 3 weeks. Mean counts of particles with sizes between 1.6 and 25.4 mu increased over time for each treatment group. Within treatments, concentrated admixtures had significantly greater particle counts than the corresponding standard admixtures. Within the standard and within the concentrated admixtures, the particle counts were significantly greater for group one than for group three. Particle counts in group two tended to lie between the values of group one and three. Visual signs of emulsion deterioration were greatest in those admixtures in which the pH was not adjusted and occurred earlier in concentrated admixtures.     

Optimisation des apports phosphocalciques dans les solutions de nutrition parentérale pédiatrique

Aim of the study. – In regards to the recurrent problem of the poor compatibility between calcium and phosphorus in paediatric parenteral nutrition admixtures, the aim of this experimental study was to compare the solubility of two phosphorus salts, namely the phosphate of potassium and the glucose-1- phosphate. Either one or the two of them were mixed together with calcium in parenteral nutrition solutions.Materials and method. – The solubility of the calcium phosphate was tested in 18 nutrient admixtures having different compositions (glucose: 200 g/L, aminoacids: 10 to 30 g/L, sodium: 30 mmol/L, potassium: 31 mmol/L, calcium: 12 to 25 mmol/L, phosphorus: 20 to 30 mmol/L, magnesium: 3 mmol/L, trace elements). The solubility was studied by visual observation and by measure of the particulate contamination and was rated according to the phosphorus salt used: phosphate of potassium, glucose-1-phosphate or these two salts mixed.Results. – Concentrations of 20 mmol of calcium and 30 mmol of phosphorus can be obtained in parenteral nutrition admixtures (containing 2% of amino acids) if the initial input of phosphorus is of the form of the GP. On the other hand, these concentrations are incompatible when using the phosphate of potassium because a precipitate occurs.The specifications of the european pharmacopeia are respected: for the particulate contamination, the number of particles with a diameter ≥ 10 μm is for all the tested admixtures lower than 5 particles/ml (standard: ≤ 25 particles/ml) if the GP represents at least 50% of the initial phosphorus input.Conclusion. – The results of this study confirm that the solubility of the phosphorus regarding to calcium is increased with the glucose-1-phosphate.The calcium and phosphorus needs for the children in parenteral nutrition can be covered while limiting the iatrogenic complications.     

Infection control of parenteral nutrition solutions

Microbial contamination of parenteral nutrition solutions is a preventable cause of in patients receiving nutrition support. The components of the parenteral nutrition solutions have variable microbial growth potential. Crystalline amino acid and dextrose solutions are poor growth media for bacteria but may support fungal growth. Lipid emulsions provide an excellent medium for growth of bacteria and fungal species. Total nutrient admixtures will support microbial growth better than standard parenteral nutrition solutions will but less well than will lipid emulsion alone. Control of infection related to contaminated infusate depends on compounding procedure, quality control, appropriate storage, and procedures to prevent in-use contamination. Guidelines are presented for the preparation and administration of parenteral nutrition infusates that will minimize microbial contamination.     

Compounding TPN admixtures: then and now

Compounding TPN admixtures has significantly developed since the first clinical reports by Dr. Dudrick and colleagues from the University of Pennsylvania approximately 35 years ago. Today, the responsibility for the compounding of sage parenteral nutrition admixtures for patients incapable of oral or enteral nutrition primarily rests with the pharmacy department. Although others may influence the desirable components to be contained therin, no one is more qualified to deal with the physicochemical issues and aseptic technique compounding requirements than a registered pharmacist. In fact, the United States Pharmacopeia (USP) , the official drug compendium in the US since 1906, has published Chapter 797 entitled "Pharmaceutical Compounding--Sterile Preparations", enforceable by the FDA, and makes clear the role of the pharmacist in the compounding of safe parenteral admixtures. Ultimately, after careful pharmaceutical review of the final formulation, the composition of the final admixture for infusion will be determined based on the ability to safely compound the prescribed additives in the desired quantities of a specified volume of sterile fluid. There will always be instances, where, for example the patient's needs cannot be safely met through the TPN admixture, primarily because of stability, compatibility and/or sterility issues. When this occurs, suitable alternative methods of delivering the additives in question must be sought so as not to compromise the safety issues of the final TPN infusion. Although there have been many advances in the development of nutritional additives, compounding devices, and containers, significant safety issues continue to arise necessitating further modification of paretneral nutrition protocols. ASPEN, through periodic reviews of tis published guidelines, such as the 1998 Safe Practices for Parenteral Nutrition Formulations, is in a key position to keep nutrition support clinicians abreast of the central issues affecting the safety of TPN therapy.(Journal of Parenteral and Enteral Nutrition     

Enteral feeding

In this review, topics with scientific strength, topical interest, and controversy were selected. Over the past 50 years, malnutrition has become increasingly recognized as a cause of increased morbidity and mortality in hospital patients. From 1970 to 1980, parenteral nutrition was advocated as the most appropriate form of nutritional therapy for hospital patients. Since then, parenteral nutrition has been replaced by enteral nutrition as the best way of delivering nutrients to hospital patients. The timing of enteral nutrition has been debated. Should it be instituted early, within the first 24 hours? In addition, enteral nutrition containing immune-enhancing nutrients such as arginine, omega-3 fatty acids, glutamine, and nucleotides has been advocated for critically ill patients. The relative merits of enteral versus total parenteral nutrition continue to be debated. Questions about possible complications related to enteral nutrition have been raised. Patients are at risk of nosocomial pneumonia from aspiration and at risk of bowel ischemia because enteral nutrition increases intestinal oxygen consumption. Steroids are often used to treat Crohn disease, but because of undesirable side effects, various techniques have been used to reduce steroid dependency. Enteral nutrition has been advocated as a way of reducing steroid dependency. Finally, enteral nutrition is routinely used to feed demented patients and those in a vegetative state. It is not clear whether this practice alters outcome or quality of life.     

药师与临床营养支持

美国肠外肠外营养学会建议由医师、营养师、护师和药师组成一个联合小组,共同完成临床营养支持工作,以确保每位病人接受到最适宜的全方位服务。药师的参与可以提高效用、降低副作用和费用,我们体会可以从以下几方面做些工作：（1）处方的审查和标签：既注意营养组分的量,也关注配成TNA后各组分的实际浓度,使处方配比合理化,协助医师真正实现个体化给药。（2）配制环境及技术：严格执行无菌操作基本原则,从处方设计到配制操作过程都应有质量保证即质量管理活动贯穿于全过程。临时配制最好由经过专门训练的合格人员来承担。不同配伍的、不稳定的或污染的静脉输液会显增加病人的致病率甚至死亡率。药剂科应成立有专人负责的一个小组并建立相应的规章制度和操作规程。（3）PN的配伍和稳定性：关注配制时间、储存周期、营养组分相互作用和包装材料对组分稳定性影响,防止不溶性微粒和乳析现象的发生。尽量避免将药物配伍入PN液中,关注包括Y型管在内的配伍变化。（4）PN混合液的在线过滤：建议使用终端滤器,防止输注过程的危害。0．2μm的滤器可用于一般输液,1．2μm的滤器适于含脂肪乳的PN液。选择膜滤器时不应考虑膜的耐受范围。（5）肝素问题：肝素会降低脂肪乳的稳定性。（6）导管：药师应注意导管对药物的吸附、导管添加剂的游离释出和导管入口处的消毒问题。（7）材料与包装容器的影响：包装材质、热压灭菌过程和不同品牌市售产品对PN液的稳定性和配伍的影响都应注意。（8）药师也应关注肠内营养,协助医师做好患营养支持过渡工作,并注意下胃管给药时的一些稳定性问题。     

Folic acid and total parenteral nutrition

The stability of folic acid in a variety of solutions used for parenteral nutrition has been determined over a 2-wk period. Provided that the acidity of the solution remains above pH 5.0 the folate, in the concentrations usually used for parenteral nutrition, will remain stable in solution, and all of the folate added to the solution will be delivered to the patient. The applicability of this in vitro work to a group of patients requiring parenteral nutrition was assessed, in order to determine a suitable dose. A dose of 0.2 mg of folic acid daily was inadequate to meet the requirements of these patients. In contrast a dose of 1.2 mg daily for 7 days was sufficient to cause an increase in the serum folate concentration.     

Potential usefulness of olive oil-based lipid emulsions in selected situations of home parenteral nutrition-associated liver disease

Long-term (i.e. home) parenteral nutrition has been advocated to be responsible for several metabolic complications among which hepatic disorders have long been the most relevant in view of patients' prognosis. The increased knowledge of the pathophysiologic factors associated to parenteral nutrition-related liver disease as well as the regular improvement of the components and the techniques used for parenteral nutrition leaded progressively to a better prevention of these side effects. This case report focuses on the potential interest of olive oil-based lipid emulsions in home parenteral nutrition patients, in selected situations of home parenteral nutrition-associated metabolic liver disease.     

Particulate contamination in parenteral nutrition solutions: still a cause for concern?

OBJECTIVES: In consideration of a US Federal Drug Administration recommendation that all parenteral nutrition admixtures should be administered through an in-line filtration device, this observational study examined the number, size distribution, and sources of particulate contamination in parenteral nutrition admixture infusion systems. METHODS: Samples were drawn from the terminal connection of the infusion tubing before connection to the patient. The particles were sized and counted by optical microscopy and further investigated by electron microscopy and energy disperse spectroscopy. RESULTS: Large numbers of particles were found, and information gained about their possible origin. CONCLUSIONS: This study provides further support for the adoption of this Federal Drug Administration recommendation.     

A simple equation to estimate the osmolarity of neonatal parenteral nutrition solutions

A predictive equation of osmolarity that correlates closely with the measured osmolality was determined. Taking into account that an osmometer is not available in most clinical settings, the proposed equation appears to provide a quick and simple osmolarity calculation of neonatal parenteral nutrition solutions. OBJECTIVE: We measured the osmolalities of neonatal parenteral nutrition (PN) solutions to determine if these values may be predicted by a simple equation for calculation of their osmolarity values. METHODS: The osmolalities of 101 consecutive different final PN admixtures, prepared for 36 neonates, were measured by the freezing point depression method. The respective intra-assay and interassay coefficients of variation were always <2.1%. Linear multivariate regression analysis was used to determine a predictive equation of osmolarity that correlates closely with the value of measured osmolality. RESULTS: The mean (SD) osmolality of the final PN admixtures was 749.7 (165.4) mOsm/kg. The best-fitted equation, with a coefficient of discrimination R2 = .95 (R2 = .90 for samples between 500 and 1000 mOsm/L) is osmolarity (mOsm/L) = (nitrogen x 0.8) + (glucose x 1.235) + (sodium x 2.25) + (phosphorus x 5.43)-50, with the concentration of components in mmol/L. Adapting the equation in our daily practice, using g/L for glucose and amino acids, mg/L for phosphorus, and mEq/L for sodium, the equation is osmolarity (mOsm/L) = (amino acid x 8) + (glucose x 7) + (sodium x 2) + (phosphorus x 0.2) - 50, with a similar R2. CONCLUSIONS: Taking into account that an osmometer is not available in most clinical settings, the proposed equation appears to provide a quick and simple osmolarity calculation of neonatal PN solutions, thus allowing more accurate decisions to be taken regarding the choice of route and rate of administration of PN solutions.