Total Parenteral Nutrition Admixtures Research Articles

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

ObjectivesThe 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. MethodsThe 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. ResultsTwo-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. ConclusionsThe 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.

P21 Scurvy during home parenteral nutrition

IntroductionDegradation of ascorbic acid due to oxygen presence in parenteral nutrition (PN) is well documented.1 Although patients on home parenteral nutrition (HPN) are routinely monitored for some vitamin deficiencies, plasma vitamin C is rarely measured in this population.We report a case of clinical vitamin C deficiency in a patient with severe dysmotility for whom the only source of nutrition was parenteral nutrition with continuous infusion over 24 hours.MethodsA 6 years old girl with severe gastrointestinal dysmotility following a fundoplication tolerated no enteral feed and could not have time off PN due to hypoglycaemic episodes. She presented with gingival bleeding and epistaxis and also complaining of pain on her arms and shoulders. A clotting was requested which showed prolonged INR and she was treated with IV vitamin K. An x-ray of her wrist and shoulder showed osteopenia but no other abnormalities. Vitamin C measurement was requested.ResultsPlasma vitamin C was low at 3.5 micromol/L (26.1–84.6) which confirmed the diagnosis of scurvy. She was treated with 3 doses of Pabrinex® over 3 days (providing total of 450 mg vitamin C). 100 mg of ascorbic acid were also added to her PN, providing double the baseline amount. Plasma vitamin C measured after two weeks had risen to normal at 45 micromol/L. Her bleeding and pains resolved over a few days. During the next year plasma vitamin C was measured every three months and remained within reference range. She remained clinically well with no recurrence of bleeding. Due to methodology limitations, the amount of vitamin C in the PN bag could not be tested. Therefore we decided to measure plasma vitamin C in two other patients that had PN as the only source of nutrition and given over 12 hours. In both cases the result was within the reference range at 58.7 and 38 micromol/L respectively. Published literature2 suggests that temperature contributes to vitamin C degradation. The PN fluid would have been at room temperature for around 24 hours for the patient that developed scurvy, compared to half this time in the other two.ConclusionsThis case highlights that there is a significant risk of vitamin C degradation due to the oxygen present within the PN bag. However, the fact that for the other 2 patient’s plasma vitamin C was normal suggests that presence of oxygen alone might not be enough to cause vitamin C insufficiency. Temperature might be a contributing factor to vitamin C degradation, as has been shown with enteral feed.3 From these cases we concluded that measurement of vitamin C during HPN would be indicated not only if there were suggestive symptoms, but should also be added in to routine monitoring in any patient with a 24 hour infusion time and extremely restricted enteral intake.ReferencesNHS Pharmaceutical Quality Assurance Committee, Standard protocol for derivation and assessment of stability Part 4 – Parenteral Nutrition, May 2016Turmezei J, Javorszky E, Szabo E, et al. Effect of storage temperature on stability of total parenteral nutrition admixtures prepared for infants. Acta Poloniae Pharmaceutica, Drug Research 2015:72:843–9Gorman SR, Armstrong G, Allen KR, et al. Scarcity in the midst of plenty: enteral tube feeding complicated by scurvy. Journal of Pediatric Gastroenterology and Nutrition 2002;35:93–95

Investigation of short-term stability of parenteral nutrition nanoemulsions prepared under laboratory conditions

Background/Aim. The application of nanoemulsions (NE) in parenteral nutrition represents a very important advancement that marked the medicine and pharmacy of the twentieth century. Over the years, the technology of the production of NE and total parenteral nutrition (TPN) nanoemulsions or admixtures has undergone constant improvement. Representing the continuation of the previous research, this paper deals with nanoemulsions in a concentration of 20% that were prepared under laboratory conditions. The main emphasis was put on the possibility of detecting the potential presence of large droplets or agglomerates of droplets that could cause fatal effects. In addition, the quality assessment of the TPN admixture containing these nanoemulsions was performed. These results were compared with the results obtained from the TPN admixture prepared from the industrial emulsion (Lipofundin MCT/LCT 20%?). Methods. During the 30-day period of monitoring nanoemulsion physical-chemical characteristics, the volume diameters that define the width of the lipid droplet size distribution were determined using the laser diffraction method. In addition, TPN physical and chemical characteristics were monitored for 72 hours and included: measurements of the mean droplet diameter, the volume diameter, distribution of the droplet size, ie. polydispersity index (PDI), ?-potential, and pH values. Results. Obtained results were in accordance with the literature data related to the quality of parenteral nanoemulsions (values of volume diameters ranged between 50 and 490 nm). TPN admixtures remained stable during the testing period, even in cases when TPN admixtures containing either a newly formed or an industrial nanoemulsion were tested. Conclusion. Characteristics of investigated nanoemulsions do not significantly alter under the ambient temperature storage. If the preparation principles and the component mixing order are followed, TPN admixture possessing satisfactory physical and chemical quality and stability can be obtained.

Development, Validation, and Stability Assessment Application of RP-HPLC-DAD Method for Quantification of Ampicillin in Total Parenteral Nutrition Admixtures.

Background: The administration of total parenteral nutrition (TPN) is a common procedure in intensive care units, where the concomitant use of other intravenous medication is frequently needed. One of the particularly dangerous complications for neurosurgical patients is meningitis, for which high doses of ampicillin (AMP) are used. In such cases, the addition of AMP to TPN admixtures would be a desirable procedure. Thus, the AMP determination method in TPN admixture was developed and validated. Methods: An isocratic HPLC analysis was performed on a LiChrospher C18 end-capped column (250 mm, 4.6 mm, 5 µm) with a C18 pre-column (LiChrospher 100, 4 mm, 5 µm). The flow rate was 1.0 mL min−1 and the detection wavelength was 230 nm. System suitability parameters, such as capacity factor, numbers of the theoretical plate, asymmetry factor, as well as validation parameters, including method precision, accuracy, linearity, selectivity, and robustness, were set up. Results: The method was shown to be linear, precise, accurate, specific, and robust, and it can be used for the quantitative analysis of AMP in TPN admixtures. Conclusions: The degradation of AMP in the TPN admixtures occurred according to first order kinetics. The degradation rate was high and dependent on the composition of the mixture and the storage conditions (t0.5 varied from 142.44 h to 300.45 h).

Effect of Lipid Emulsion on Stability of Ampicillin in Total Parenteral Nutrition.

Background: Ampicillin (AMP) is frequently administered parenterally in critically ill patients with meningitis or endocarditis. Many of them require parallel infusion of total parenteral nutrition (TPN) admixtures. The aim of the study was to determine the physicochemical stability of AMP in TPN admixtures. Methods: AMP was added to two formulations of TPN admixtures differing in the lipid emulsion (Lipofundin® MCT/LCT 20% or LIPIDem®). Samples were stored at 4 ± 1 °C with light protection, and at 25 ± 1 °C with and without light protection to assess the impact of temperature and light on formulation stability. Every 24 h the pH, zeta potential, mean droplet diameter (MDD) of a lipid emulsion, and AMP concentration using HPLC method were determined. The assessment of stability and compatibility of TPN admixtures with vitamins and trace elements was carried out immediately after preparation and after 24 h of storage. Results: The addition of AMP as well as vitamins and trace elements to the TPN admixtures did not affect their physical stability. An increase in the pH value of approx. 0.6 and reduction of zeta potential were observed. The MDD of the lipid emulsions was below the limit of 500 nm (dynamic light scattering (DLS) method) and no fat droplets greater than 525 nm were observed (light diffraction (LD) method). The content of AMP after the first 24 h was within the acceptable limit of 90% for TPN admixtures stored at 4 ± 1 °C and 25 ± 1 °C with light protection. Conclusions: The results showed that co-administration of AMP in the same bag with TPN admixture at the tested dose is possible when used ex tempore and with light protection.

Physical stability of an all-in-one parenteral nutrition admixture for preterm infants upon mixing with micronutrients and drugs

ObjectivesThe main objective was to investigate Y-site compatibility of intravenous drugs with one standard total parenteral nutrition (TPN) admixture for preterm infants. Since micro-precipitation was observed in the water phase...

Experience of compounding total parenteral nutrition admixtures for preterm infants in a hospital pharmacy: evidence of calcium and phosphate compatibility problem

ObjectiveParenterally fed preterm newborn infants require large amounts of calcium and phosphate in a low volume of solution. The lower the volume of solution, the higher is the possibility of...

Efficacy and safety of free iron in total parenteral nutrition (TPN) admixtures : an experimental study in rats

Efficacy and safety of free iron in total parenteral nutrition (TPN) admixtures : an experimental study in rats

Physical compatibility of total parenteral nutrition and drugs in Y-site administration to children from neonates to adolescents.

Infusion of precipitate or destabilized emulsion can be harmful. The purpose of this study was to obtain Y-site compatibility data on intravenous drugs and total parenteral nutrition (TPN) relevant for children. Two three-in-one TPN admixtures (Olimel N5E and Numeta G16E) used for children of different age groups were tested with ten drugs (ampicillin, ceftazidime, clindamycin, dexamethasone, fluconazole, fosphenytoin, furosemide, metronidazole, ondansetron and paracetamol). Drug : TPN ratios were estimated from a wide range of age and weight classes, and the most extreme mixing ratios (drug > TPN, TPN > drug) in addition to 1 + 1 were chosen. Assessment of potential precipitation was performed by subvisual particle counting, visual examinations and measurements of turbidity and pH. Emulsion stability was investigated by estimation of percentage of droplets above 5 μm (PFAT5), mean droplet diameter and pH measurements. Complimentary theoretical evaluations were performed. Ampicillin, fosphenytoin and furosemide precipitated when mixed with TPN. The results for ceftazidime, clindamycin, dexamethasone, fluconazole, metronidazole, ondansetron and paracetamol suggest that they were compatible with either TPN in the tested concentrations. None of the drugs were found to destabilize the emulsions. Three drugs showed clear signs of precipitation when mixed with TPN and these products should not be co-administered in the same infusion line.

Development and evaluation of a test program for Y-site compatibility testing of total parenteral nutrition and intravenous drugs

BackgroundThere is no standardized procedure or consensus to which tests should be performed to judge compatibility/incompatibility of intravenous drugs. The purpose of this study was to establish and evaluate a test program of methods suitable for detection of physical incompatibility in Y-site administration of total parenteral nutrition (TPN) and drugs.MethodsEight frequently used methods (dynamic light scattering, laser diffraction, light obscuration, turbidimetry, zeta potential, light microscopy, pH-measurements and visual examination using Tyndall beams), were scrutinized to elucidate strengths and weaknesses for compatibility testing. The responses of the methods were tested with samples containing precipitation of calcium phosphate and with heat destabilized TPN emulsions. A selection of drugs (acyclovir, ampicillin, ondansetron and paracetamol) was mixed with 3-in-1 TPN admixtures (Olimel® N5E, Kabiven® and SmofKabiven®) to assess compatibility (i.e. potential precipitates and emulsion stability). The obtained compatibility data was interpreted according to theory and compared to existing compatibility literature to further check the validity of the methods.ResultsLight obscuration together with turbidimetry, visual inspection and pH-measurements were able to capture signs of precipitations. For the analysis of emulsion stability, light obscuration and estimation of percent droplets above 5 μm (PFAT5) seemed to be the most sensitive method; however laser diffraction and monitoring changes in pH might be a useful support. Samples should always be compared to unmixed controls to reveal changes induced by the mixing. General acceptance criteria are difficult to define, although some limits are suggested based on current experience. The experimental compatibility data was supported by scattered reports in literature, further confirming the suitability of the test program. However, conflicting data are common, which complicates the comparison to existing literature.ConclusionsTesting of these complex blends should be based on a combination of several methods and accompanied by theoretical considerations.

An RP-HPLC-UV Method with SPE for Cefotaxime in All-in-One Total Parenteral Nutritional Admixtures: Application to Stability Studies

A simple and selective RP-HPLC-UV method with SPE was developed and validated for the quantification of cefotaxime in all-in-one total parenteral nutrition (AIO-TPN) admixtures. Chromatographic separation was achieved on a 5 pm particle size C18 DB column (250 x 4.6 mm id) using the mobile phase ammonium acetate (25 mM, pH 4.0)-50% acetonitrile in methanol (80 + 20, v/v). The flow rate was 0.9 mL/min and the detection wavelength was 254 nm. The analyte was extracted from AIO-TPN admixtures by means of an SPE method. The cefotaxime calibration curve was linear over a concentration range of 100-1400 microg/mL with a correlation coefficient of > or = 0.9994. The intraday accuracy and precision for cefotaxime were < or = -3.15 and < or = 3.08%, respectively, whereas the interday accuracy and precision were < or = -2.48 and < or = 2.25%, respectively. The method was successfully applied to stability studies of cefotaxime in the presence of micronutrients together with low and high concentrations of macronutrients in AIO-TPN admixtures. Cefotaxime was degraded by 13.00 and 26.05% at room temperature (25 +/- 2 degrees C) after 72 h in low and high macronutrient concentration formulations of AIO-TPN admixtures, respectively. The values of cefotaxime degradation rates for low and high macronutrient concentration formulations of AIO-TPN admixtures were -0.164 and -0.353, respectively. These results indicated that there was a higher rate of degradation in the AIO-TPN admixture formulations containing high concentrations of macronutrients.

TCH-041 Stability of Total Parenteral Nutrition Admixtures For Paediatric Home Care in the Presence of High Concentrations of Electrolytes

BackgroundIn clinical practise electrolyte enrichment of the parenteral nutrition admixtures is a typical request, especially on the neonatal/paediatric wards. The supplementation of parenteral nutrition with high concentrations of electrolytes is...

Application of lean methods to compounding services in hospital pharmacy

ObjectivesTo implement, and evaluate the use of, lean methods in highly congested areas of the pharmacy department such as the clean room. Through the use of lean tools such as...

Quality assessment of total parenteral nutrition admixtures by the use of fractional factorial design

Parenteral nutrition as a specific as pect of providing nutritients still remains a permanent topic of both theoretical and experimental research. Total parenteral nutrition (TPN) admixtures have complex con tents making difficult to maintain their stability. The most critical parameter is the diameter of a lipid droplet, i.e. droplet size distribution. It is recommended that droplet size should not be more than 5 microm and that the presence of greater droplets should not exceede the value of 0.05%. Lipid droplets size is affected particularly by electrolyte addition, especially polyvalent cations. There is a danger of the added electrolytes interaction with lipid droplets which leads to their aggregation and negative effects upon the admixtures stability. The aim of this study was to as sess the effect of added electrolyte and lipid phase quan tity on the admixture stability. Electrolytes were added to the studied admixture of a defined basic formulation contents in accordance with recommenda tions from the literature. Droplets size measurements were performed using the method of laser diffraction with a laser particles analyzer. Effects of independent variables were calculated and evaluated using commercial software. Na(+), K(+), Ca(2+) and Mg(2+) concentrations, as well as the quantity of fat phase were chosen as studied fac tors, i.e. independed variables. The system response, or dependent variable was the median of droplets size. Each of the factors was varied at two levels, higher (+1) and lower (-1), according to the 2(5-2) fractional factorial design. The study suggested the presence of relative uni formity of the results of all the measurements regardless of the quantity of added electrolytes and lipid phase. It was shown that undoubtedly there is the influence of 2 valent cations (calcium and magnesium) upon lipid drop lets size, which is in a direct correlation with theoretical assumption. Within a 72-hour testing period there was no significant increase in droplet size, i.e. the studied admixtures remained stable considering droplet size median as the criterion of stability.

EAHP Survey 2010 on hospital pharmacy in Europe: Part 3. Production and quality assurance

The number of hospital pharmacies in Europe producing sterile as well as non-sterile medicines has decreased significantly since 2000. In addition, the number of pharmacies preparing total parenteral nutrition, cytotoxics...

Kinetic stability of all-in-one parenteral nutrition admixtures in the presence of high dose Ca2+ additive under clinical application circumstances

BackgroundTPN infusions are usually administered during a treatment period of 10–24 hours per day due to the metabolic capacity of the liver. During this time interval physicochemically stable TPN solution (emulsion) is needed for the treatment. The purpose of the present study was to examine how the kinetic stability features of ready-made total parenteral nutrition admixtures containing olive oil and soybean oil will change under the usage-modeling 24-hour application with and without overdose Ca2+.MethodsParticle size analysis and zeta potential measurements were carried out to evaluate the possible changes in the kinetic stability of the emulsions.ResultsOur results indicate that in two of the four mixtures bimodal droplet-size distribution figures were detected and appearance of fat particles over 5 μm can not be disclosed. The tendency for separation of large diameter droplets in the two types of oil-based emulsion systems was different. In case of soybean containing emulsion second peak of droplets appeared in the bottom of the container in contrast to the olive oil containing emulsions where the second peak appeared in the surface layer. Interestingly this phenomenon is independent of calcium-content.ConclusionsFrom therapeutic point the emulsions of the bigger droplets containing upper layer are safer because the potentially dangerous big droplets could remain in the infusion bag after the administration.

Inflammatory Response in Preterm Infants Is Induced Early in Life by Oxygen and Modulated by Total Parenteral Nutrition

The i.v. lipid emulsion (LIP) is a source of oxidants, which may stimulate inflammation. Coadministration of parenteral multivitamins (MVP) with LIP prevents lipid peroxidation in light-exposed total parenteral nutrition (TPN). We hypothesized that this modality of TPN administration affects systemic inflammation, which may be modulated by exposure to oxygen. Premature infants were allocated to three TPN regimens: control regimen - MVP coadministered with amino acid/dextrose exposed to ambient light, LIP provided separately (n = 9) - LIP+MVP light exposed (LE): MVP coadministered with light-exposed LIP (n = 9) - LIP+MVP light protected (LP): MVP coadministered with light-protected LIP (n = 8). In LE and LP, amino acid/dextrose was provided separately. On reaching full TPN, infants were sampled for IL-6 and IL-8 in plasma and the redox potential of glutathione in whole blood (E, mV). Data were compared (ANOVA) in infants exposed to low (<0.25) versus high (> or =0.25) FiO2. Patients (mean +/- SD: birth weight 797 +/- 172 g; GA 26 +/- 1 wk) had similar clinical characteristics in TPN groups. Cytokine levels correlated positively (p < 0.01) with FiO2 and E. High FiO2 stimulated an increase (p < 0.01) in cytokines in control regimen, whereas these markers remained unaffected by oxygen in the LE and LP groups. The choice of a TPN admixture may have important consequences on the systemic inflammatory response triggered by an oxidant stress.

Physical compatibility of neonatal total parenteral nutrition admixtures containing organic calcium and inorganic phosphate salts in a simulated infusion at 37°C*

Within an incubator environment at 37 degrees C, we evaluated the physical compatibility of calcium (Ca) and phosphate (P) in simulated neonatal total parenteral nutrition (TPN) infusions. Representative neonatal TPN formulas containing four concentrations of amino acids [AA] (1-4 g/dL) and two levels of dextrose [D] (5 and 10 g/dL) were monitored for calcium-phosphate precipitate formation over 24 hours using a laser-based particle counting technique. Research Laboratory. None. Of the eight AA-D combinations studied, two formulas containing 1 g/dL AA with either 5 g/dL or 10 g/dL of D and high amounts of Ca and P resulted in significant increases in particle counts and visibly evident precipitation during the 24-hour infusion. Precipitation was noted only after the infusion passed through the incubator, but not in the TPN bags, demonstrating the heightened risk of calcium-phosphate incompatibility with increased temperatures. Low AA concentrations and high temperatures are significant risk factors for the precipitation of the insoluble dibasic calcium phosphate that may be fatal upon intravenous infusion. When thermoregulation is required, the AA concentration of the TPN formula should not be less than 1.5 g/dL (and ideally > or =3 g/dL) when high intakes of calcium (60 mg/dL) and phosphate (46.5 mg/dL) are prescribed.

Molecular dynamics simulation of a mixed lipid emulsion model: Influence of the triglycerides on interfacial phospholipid organization

The lipid droplets, in total parenteral nutrition admixtures, are composed of triglycerides surrounded by a phospholipid monolayer. Physicochemical interactions between lipids and the other components are critical for the emulsion stability. To assess these interactions at the molecular level, we have constructed a model of a mixed phospholipid monolayer at the oil–water interface mimicking the lipid droplet surface. Physico-chemical properties of this model are computed by molecular dynamics simulations, and surface pressure–surface area compression isotherms at the air/water interface were recorded in order to compare experimental data to calculated area values. Both phospholipid and triglyceride phases are mixtures close to the composition of the commercial Ivelip ® 20% lipid emulsion. In the studied model, the triglyceride phase is formed of 191 triglyceride molecules of four different formulas and each monolayer is composed of 100 molecules of five different zwitterionic or anionic phospholipids. Mixing of different phospholipids has a strong influence on the molecular area and modifies the hydrogen bonding network within the interface. Comparison of the mixed monolayer to a bilayer with the same phospholipid composition demonstrates that the triglycerides play an important role on the interfacial properties of the system. Phospholipid polar headgroups appear more hydrated, molecular area is larger, and lipid tails more disordered in the simulated lipid emulsion model than in the bilayer. The electrostatic potential, however, is the same. Taken together, these results demonstrate the utility of this mixed monolayer model at the oil–water interface instead of a hydrated bilayer model for studying lipid–cations interactions. These simulations are a starting point for further studies where the role of calcium will be analyzed.

Stability investigation of total parenteral nutrition admixture prepared in a hospital pharmacy

In the cases when nutrition of patients can not be orally nor enterally performed, parenteral nutrition is a method of the therapy that provides more successful and rapid recovery. In that way, hospitalization can be significantly shorter, healing costs reduced and mortality minimized. Total parenteral nutrition (TPN) admixtures are the most complex systems which contain amino acids, carbohydrates, lipid emulsion, macroelectrolytes (Na+, K+, Ca2+, Mg2+, Cl(-), SO4(2-), PO4(3-)), oligoelements, hydro- and liposoluble vitamines, heparin, insulin and water. Concerning the mentioned complexity, special attention should be payed to physicochemical and microbiological stability of a mixture, because of interactions among components, that can be very hard to analyze. The aim of this study was to investigate the problem of stability of TPN admixtures prepared in a hospital pharmacy. Admixture TPN was aseptically prepared in laminar air--flow environment on the basis of the specified order in supplementing components and additives to basic solutions. Solutions were kept in sterile multicompartment ethylene-vinyl-acetate bags. After preparation and slow homogenization, TPN admixtures were submitted to physicochemical and microbiological stability analyses in various period of time. The assessment of physical stability of TPN admixture was done on the basis of visual inspection, determination of pH value and measuring of particle size. The investigation of sterility and pyrogenic test were performed according to Ph. Yug. V regulations. Physico-chemical and microbiological analyses were applied and no significant changes in visual sense, pH value and droplet size stability of the TPN admixture were observed during the period of 60 hours The lipid droplets were smaller in size than 5 microm, that is the most common pharmacopoeia requirement. The results of our study confirmed that a TPN admixture prepared in a hospital pharmacy can be stored without stability loss for at least 60 hours.