Intravenous Lipid Emulsions in the NICU.

The clinical goals of intravenous lipid emulsions (ILEs) have changed since their initial development. In the past, 100% soybean oil was used to provide energy and prevent an essential fatty acid deficiency. Now, different oil sources are used with the goal of improving nutritional status and preventing common neonatal comorbidities. We now have a better understanding of specific ILE constituents, namely, fatty acids, vitamin E, and phytosterols, and how these components contribute to complications such as intestinal failure-associated liver disease. This review addresses the development and composition of different ILEs and summarizes how individual ILE ingredients affect infant metabolism and health.

Physicochemical Stability and Sterility of Standard Parenteral Nutrition Solutions and Simulated Y-Site Admixtures for Neonates.

BACKGROUND: Parenteral nutrition (PN) is frequently needed in neonatal intensive care. The use of standard PN has emerged as an easy-to-prescribe approach that allows one to have on-site, ready-to-use PN. The aim of this study was to test the physicochemical stability and sterility of 2 specific PN solutions as well as simulate Y-site compatibility with lipid injectable emulsions (ILE). METHODS: Our study considered 2 standard ILE-free PN solutions according to neonatal weight. These solutions were prepared in duplicate and stored at 4°C. The following physicochemical parameters were tested: visual alterations, turbidity, pH, osmolarity, and calcium concentration. Sterility was assessed by means of agar blood culture and glucose concentration determination. In addition, we assessed the stability of simulated Y-site admixtures. For each standard ILE-free PN solution, 2 3-in-1 PN admixtures were designed, considering extreme values of fluid requirements (50 and 150 ml/kg/d) and a fat supply of 2 g/kg/24 h. The physicochemical parameters tested were phase separation and fat mean droplet size distribution. RESULTS: No alterations were detected by visual inspection. Calcium concentrations, turbidity, pH, and osmolarity values remained stable in all the determinations. All agar blood cultures were negative and glucose concentration was constant over time. Physical stability of simulated Y-site admixtures was considered acceptable as mean droplet size distribution remained below 500 nm in all the emulsions. CONCLUSION: The 2 tested standard ILE-free PN solutions for neonates are physicochemically stable and sterile for 31 days under refrigeration (4°C). These solutions are also stable in case of Y-site administration with ILE at the conditions tested.

Physicochemical stability and compatibility testing of levetiracetam in all-in-one parenteral nutrition admixtures in daily practice.

BACKGROUND: Parenteral antiepileptic drugs are frequently used in critically ill patients for seizure control therapy or prevention. Many of these patients require additional parenteral nutrition (PN). Therefore, a parallel infusion of the frequently used antiepileptic drug levetiracetam (LEV) is interesting in terms of the restricted i.v. lines (e.g., neonates). The potential interactions of the complex PN admixture with the drug product and the appropriate admixing of a drug at effective dosages require physicochemical lab assessments to obtain specific and reliable pharmaceutical documentation for the intended admixing. AIM: To assess the of compatibility and stability of LEV, a neutral and hydrophilic drug, in commercial all-in-one (AiO) PN admixtures using simple validated tests to provide necessary data in a timely manner and to allow convenient, documented and safe treatment with PN as the drug vehicle. METHODS: Different concentrations of LEV were injected into two different AiO PN admixtures with no further additives. Stability and compatibility tests for the drug and the PN admixtures were performed over seven days at +4°C, +23±1°C and +37°C without light protection. Stability and sample characteristics were observed by visual inspection and the validated light microscope method. Moreover, the pH level of the admixture was checked, as were the concentrations of LEV over time in the PN admixtures, using an established LC-MS/MS method. RESULTS: The stability controls of LEV at different temperatures were within absolute ±20% of the theoretical value in a concentration range of 98.91-117.84% of the initial value. No changes in pH occurred (5.55±0.04) and no microscopic out of specification data or visual changes were observed. The mean value of the largest lipid droplet in each visual field over seven days was 2.4±0.08µm, comparable to that of the drug-free AiO admixture. Samples stored at +37°C showed yellowish discolorations after 96h of storage. CONCLUSION: LEV showed compatibility and stability over seven days in the selected PN admixtures, and the described methods represented a valuable and timely approach to determine the stability and compatibility of the highly hydrophilic, not dissociated LEV in AiO admixtures under conditions of use. Further studies with clinically relevant and representative examples of physicochemically different drug classes are needed.

Use of intravenous lipids: what do the guidelines say?

The use of intravenous lipids is very frequent in most parenteral nutrition (PN) prescriptions. In this chapter, a systematic review of the literature was performed to compare the position of the various scientific societies (mainly the European Society for Clinical Nutrition and Metabolism, the American Society for Parenteral and Enteral Nutrition, and the German and Canadian Nutrition Societies) in terms of recommendations of when intravenous lipids should be prescribed for different clinical conditions. These recommendations may be supported by strong evidence or, if not available, by expert opinion. These recommendations help the physician in his daily prescription of PN in the hospital and help the patient requiring home PN.

Assessment of the physicochemical stability of all-in-one parenteral emulsions for neonates according to USP specifications.

BACKGROUND: The purpose of this study was to describe the methodology to assess the stability of all-in-one (AIO) parenteral nutrition admixtures, containing glucose, proteins, and lipids, to the standards of U.S. Pharmacopoeia (USP <729>). The influence of calcium and commercially available lipid emulsions and amino acid solutions were also examined. METHODS: Four batches of 5 AIO admixtures containing calcium were compounded with commercially available lipid emulsions and amino acid solutions. Two of them contained calcium. Their stability was tested under conditions simulating clinical use. All the admixtures were assessed for criteria set by the USP <729>: (1) mean droplet diameter (MDD) and (2) percentage of volume weighted particles with diameter > 5 µm (PFAT5). RESULTS: All admixtures were within the specifications set by the USP with respect to the MDD at 0, 24, and 48 hours, but only those batches lacking calcium met the benchmarks set by the pharmacopoeia, with respect to PFAT5, on the day of preparation. CONCLUSIONS: The presence of calcium destabilized the admixtures, while the use of different commercial ingredients altered the admixtures' characteristics. Only 1 batch of the AIO admixtures studied was found to be compliant with USP <729> standards.

Fat emulsions as diffusive reference standards for tissue simulating phantoms?

Intralipid 20% was recently suggested as a diffusive reference standard for tissue simulating phantoms. In this work, we extend previously obtained results to other fat emulsions, specifically Intralipid 10%, Intralipid 30%, Lipovenoes 10%, Lipovenoes 10% PhosphoLipid Reduced, Lipovenoes 20%, Lipofundin S 10%, and Lipofundin S 20%. Of particular importance for practical applications, our measurements carried out at a wavelength of 751 nm show the following features. First, these products show high stability and small batch-to-batch variations in their diffusive optical properties, similar to Intralipid 20%. Second, the absorption coefficient of Intralipid, Lipovenoes, and Lipofundin S are very similar and their measured values are within the experimental errors; moreover the reduced scattering coefficient of Intralipid 20%, Lipovenoes 20%, and Lipofundin S 20% are similar and their measured values are within 5%. Third, the reduced scattering coefficient of Intralipid 10% and Intralipid 30% can be scaled from that of Intralipid 20% with an error of 9% and 2%, respectively. A similar scaling property is valid for Lipovenoes and Lipofundin S. We have verified that this scaling property depends on the composition of the fat emulsions: If the ingredients exactly scale with the concentration then the reduced scattering coefficient almost exactly scale as well.

Droplet-size distribution and stability of commercial injectable lipid emulsions containing fish oil.

PURPOSE: The droplet size of commercial fish oil-containing injectable lipid emulsions, including conformance to United States Pharmacopeia (USP) standards on fat-globule size, was investigated. METHODS: A total of 18 batches of three multichamber parenteral products containing the emulsion SMOFlipid as a component were analyzed. Samples from multiple lots of the products were evaluated to determine compliance with standards on the volume-weighted percentage of fat exceeding 0.05% (PFAT(5)) specified in USP chapter 729 to ensure the physical stability of i.v. lipid emulsions. The products were also analyzed to determine the effects of various storage times (3, 6, 9, and 12 months) and storage temperatures (25, 30, and 40 °C) on product stability. Larger-size lipid particles were quantified via single-particle optical sensing (SPOS). The emulsion's droplet-size distribution was determined via laser light scattering. RESULTS: SPOS and light-scattering analysis demonstrated mean PFAT(5) values well below USP-specified globule-size limits for all the tested products under all study conditions. In addition, emulsion aging at any storage temperature in the range studied did not result in a significant increase of PFAT(5) values, and mean droplet-size values did not change significantly during storage of up to 12 months at temperatures of 25-40 °C. CONCLUSION: PFAT(5) values were below the USP upper limits in SMOFlipid samples from multiple lots of three multichamber products after up to 12 months of storage at 25 or 30 °C or 6 months of storage at 40 °C.

Evaluation of microbial contamination associated with different preparation methods for neonatal intravenous fat emulsion infusion.

PURPOSE: Microbial contamination associated with different methods of neonatal intravenous fat emulsion (IVFE) preparation and delivery was evaluated. METHODS: Sterility testing was performed on IVFE dispensed via three different methods: (1) in the original container (n = 60), (2) repackaged into a syringe (n = 90), and (3) drawdown of the original container (n = 60). At the end of each infusion (24 hours for methods 1 and 3, 12 hours for method 2), a sample of the IVFE was withdrawn from the container using a sterile syringe in an International Organization for Standardization class 5 hood and sent to the hospital microbiology laboratory, where the samples were introduced into blood culture bottles and incubated for five days. Each sample was then subcultured on a blood agar plate with olive oil and left for an additional two days in a carbon dioxide incubator to assess for Malassezia furfur. RESULTS: None of the samples from the original containers showed bacterial or fungal growth. Three of the samples from syringes had bacterial growth (two samples contained coagulase-negative staphylococcus and one contained both Klebsiella oxytoca and Citrobacter freundii), yielding a contamination rate of 3.3%. The number of contaminated samples did not significantly differ among the three preparation methods (p = 0.13). CONCLUSION: Repackaging IVFE into sterile syringes resulted in bacterial contamination and should be avoided in clinical practice. IVFE samples obtained using the drawdown procedure under sterile conditions for infusion over 24 hours revealed no microbial contamination.

Stability of MCT/LCT-based total nutrient admixtures for neonatal use over 30 hours at room temperature: applying pharmacopeial standards.

BACKGROUND: United States Pharmacopeial Chapter <729> places a limit on the percentage of large fat globules >5 microm, expressed as a PFAT5 of <0.05% for all native lipid emulsions. Some adult total nutrient admixtures (TNAs) have also remained below this limit for up to 48 hours. In 2003, medium-chain/long-chain triglyceride (MCT/LCT)-based neonatal TNAs with between 2% and 3% amino acid (AA) concentrations were shown to be similarly stable by the PFAT5 parameter. Stability assessment of neonatal TNAs with AA <2% or > or =3% were tested. METHODS: Eight neonatal TNAs with various combinations of AA (1%, 1.5%, 3%, and 4%), glucose (G; 5% and 10%), and MCT/LCT (ML; 2% and 4%) and standard concentrations of additives were tested in triplicate (n = 24) over 30 hours (immediately after mixing, then at 6, 24, and 30 hours) at 25 degrees C +/- 2 degrees C. PFAT5 determinations for all 24 formulations were made in duplicate, immediately after mixing, and then at 6, 24, and 30 hours later. Mean droplet size (MDS) and pH were assessed at the outset and end of the study. RESULTS: The differences in the PFAT5 levels were significant (P < .001) by a 2-way analysis of variance based on formula and time as the independent variables. The TNAs with 1% and 1.5% AA with all Gs and MLs (group 1, n = 12) had PFAT5 levels >0.05% (up to 0.50%) in most samples (68 of 96 samples, or 71% of cases) in the study, whereas in the same TNAs, but made with 3% and 4% AA (group 2, n = 12), 100% of samples (all 96 cases) had PFAT5 levels <0.05% (up to 0.04%), and this difference was significant (P < .001). Pairwise comparisons between groups based on overall values of PFAT5, MDS, and pH showed significant differences between groups for all variables. CONCLUSIONS: For neonatal TNAs, AA level is the most sensitive determinant of stability, and the PFAT5 parameter is the most sensitive indicator of stability.

Comment to "The pharmacopeial evolution of Intralipid injectable emulsion in plastic containers: from a coarse to a fine emulsion".

The droplet size distribution of 50 batches of multi-chamber bags containing the parenteral nutrition emulsions Intralipid (Kabiven and Kabiven Peripheral) or Structolipid (StructoKabiven and StructoKabiven Peripheral), respectively, has been investigated. The results show that the non-compounded lipid emulsions analysed are in compliance with the United States Pharmacopeia (USP) chapter 729, Method II limit for the droplet size distribution, PFAT(5)<0.05%.

Nutrition therapy in the critical care setting: what is "best achievable" practice? An international multicenter observational study.

OBJECTIVE: To describe current nutrition practices in intensive care units and determine "best achievable" practice relative to evidence-based Critical Care Nutrition Clinical Practice Guidelines. DESIGN: An international, prospective, observational, cohort study conducted January to June 2007. SETTING: One hundred fifty-eight adult intensive care units from 20 countries. PATIENTS: Two-thousand nine-hundred forty-six consecutively enrolled mechanically ventilated adult patients (mean, 18.6 per site) who stayed in the intensive care unit for at least 72 hrs. INTERVENTIONS: Data on nutrition practices were collected from intensive care unit admission to intensive care unit discharge or a maximum of 12 days. MEASUREMENTS AND MAIN RESULTS: Relative to recommendations of the Clinical Practice Guidelines, we report average, best, and worst site performance on key nutrition practices. Adherence to Clinical Practice Guideline recommendations was high for some recommendations: use of enteral nutrition in preference to parenteral nutrition, glycemic control, lack of utilization of arginine-enriched enteral formulas, delivery of hypocaloric parenteral nutrition, and the presence of a feeding protocol. However, significant practice gaps were identified for other recommendations. Average time to start of enteral nutrition was 46.5 hrs (site average range, 8.2-149.1 hrs). The average use of motility agents and small bowel feeding in patients who had high gastric residual volumes was 58.7% (site average range, 0%-100%) and 14.7% (site average range, 0%-100%), respectively. There was poor adherence to recommendations for the use of enteral formulas enriched with fish oils, glutamine supplementation, timing of supplemental parenteral nutrition, and avoidance of soybean oil-based parenteral lipids. Average nutritional adequacy was 59% (site average range, 20.5%-94.4%) for energy and 60.3% (site average range, 18.6%-152.5%) for protein. CONCLUSIONS: Despite high adherence to some recommendations, large gaps exist between many recommendations and actual practice in intensive care units, and consequently nutrition therapy is suboptimal. We have identified "best achievable" practice that can serve as targets for future quality improvement initiatives.

Pharmacopeial compliance of fish oil-containing parenteral lipid emulsion mixtures: Globule size distribution (GSD) and fatty acid analyses.

Recently, the United States Pharmacopeia (USP) has established Chapter 729 with GSD limits for all lipid emulsions where the mean droplet size (MDS) must be <500 nm and the percent of fat larger than 5 microm (PFAT(5)) must be <0.05%, irrespective of the final lipid concentration. As well, the European Pharmacopeia (EP) Monograph no. 1352 specifies n3-fatty acid (FA) limits (EPA+DHA> or =45%; total n3 or T-n3> or =60%) for fish oil. We assessed compliance with USP physical and EP chemical limits of two fish oil-containing lipid emulsion mixtures. All lipid emulsions passed USP 729 limits. No samples tested had an MDS >302 nm or a PFAT(5) value >0.011%. Only one product met EP limits while the other failed. All emulsions tested were extremely fine dispersions and easily met USP 729 GSD limits. The n3-FAs profiles were lower in one, despite being labeled to contain 50% more fish oil than the other product. This latter finding suggests the n3-FA content of the fish oil source and/or the applied manufacturing processes in these products is different.

Hot topics in parenteral nutrition. Rationale for using new lipid emulsions in parenteral nutrition and a review of the trials performed in adults.

Lipids traditionally used in parenteral nutrition are based on n-6 fatty acid-rich vegetable oils such as soyabean oil. This practice may not be optimal because it may present an excessive supply of linoleic acid. Alternatives to the use of soyabean oil include its partial replacement by so-called medium-chain TAG (MCT), olive oil or fish oil, either alone or in combination. Lipid emulsions containing MCT are well established, but those containing olive oil and fish oil, although commercially available, are still undergoing trials in different patient groups. Emulsions containing olive oil or fish oil are well tolerated and without adverse effects in a wide range of adult patients. An olive oil-soyabean oil emulsion has been used in quite small studies in critically-ill patients and in patients with trauma or burns with little real evidence of advantage over soyabean oil or MCT-soyabean oil. Fish oil-containing lipid emulsions have been used in adult patients post surgery (mainly gastrointestinal). This approach has been associated with alterations in patterns of inflammatory mediators and in immune function and, in some studies, a reduction in the length of stay in the intensive care unit and in hospital. One study indicates that peri-operative administration of fish oil may be superior to post-operative administration. Fish oil has been used in critically-ill adults. Here, the influence on inflammatory processes, immune function and clinical end points is not clear, since there are too few studies and those that are available report contradictory findings. One important factor is the dose of fish oil required to influence clinical outcomes. Further studies that are properly designed and adequately powered are required in order to strengthen the evidence base relating to the use of lipid emulsions that include olive oil and fish oil in critically-ill patients and in patients post surgery.

Lipid globule size in total nutrient admixtures prepared in three-chamber plastic bags.

PURPOSE: The stability of injectable lipid emulsions in three-chamber plastic (3CP) bags, applying the globule-size limits established by United States Pharmacopeia ( USP ) chapter 729, was studied. METHODS: A total of five premixed total nutrient admixture (TNA) products packaged in 3CP bags from two different lipid manufacturers containing either 20% soybean oil or a mixture of soybean oil and medium-chain-triglyceride oil as injectable lipid emulsions were tested. Two low-osmolarity 3CP bags and three high-osmolarity 3CP bags were studied. All products were tested with the addition of trace elements and multivitamins. All additive conditions (with and without electrolytes) were tested in triplicate at time 0 (immediately after mixing) and at 6, 24, 30, and 48 hours after mixing; the bags were stored at 24-26 degrees C. All additives were equally distributed in each bag for comparative testing, applying both globule sizing methods outlined in USP chapter 729. RESULTS: Of the bags tested, all bags from one manufacturer were coarse emulsions, showing signs of significant growth in the large-diameter tail when mixed as a TNA formulation and failing the limits set by method II of USP chapter 729 from the outset and throughout the study, while the bags from the other manufacturer were fine emulsions and met these limits. Of the bags that failed, significant instability was noted in one series containing additional electrolytes. CONCLUSION: Injectable lipid emulsions provided in 3CP bags that did not meet the globule-size limits of USP chapter 729 produced coarser TNA formulations than emulsions that met the USP limits.

Droplet-size distribution and stability of lipid injectable emulsions.

PURPOSE: The droplet-size distribution (DSD) and stability of multiple lots of lipid injectable emulsions were studied. METHODS: A total of 234 commercial batches of Intralipid (Fresenius Kabi, Uppsala, Sweden) were characterized, and the influence of the emulsions' oil content on samples packaged in single- and three-chamber bags was tested. Larger-sized lipid particles were quantified using a single-particle optical sensing device. For this test, a 1-mL sample of each product was analyzed using a dilution factor of 90-400, depending on oil concentration. Analyses were performed in triplicate. Measurements were also performed in single-bag products after up to six months of storage at 23-27 degrees C and 40 degrees C. DSD measurements were determined by laser light scattering. Droplet sizes were determined using laser diffraction, with aliquots of emulsions carefully dispersed step by step applying gentle agitation. Standard deviation analyses were performed using analysis of variance. RESULTS: The volume-weighted percentage of fat droplets greater than 5 mum (PFAT(5)) values of all samples were below the large-globule size limit (0.05%) established by the United States Pharmacopeia for lipid injectable emulsions. Container volume did not significantly influence globule size, though a slight tendency for larger bag volumes to have larger PFAT(5) values was apparent. PFAT(5) and mean volume diameter values increased with oil concentration in the emulsion. Storage time and temperature had no significant effect on PFAT(5) and mean droplet-size values. CONCLUSION: Multiple lots of a lipid emulsion were found to have acceptable PFAT(5) and mean droplet-size values, regardless of oil content, container size, or storage time and tempearture.

The pharmacopeial evolution of intralipid injectable emulsion in plastic containers: from a coarse to a fine dispersion.

On December 1, 2007, the United States Pharmacopeia (USP) adopted Chapter 729 entitled Globule Size Distribution in Lipid Injectable Emulsions that contains two globule sizing methods and criteria to measure the mean droplet diameter (MDD) and the large-diameter tail of the globule size distribution to meet pharmacopeial specifications. The first of these measures, as the intensity-weighted MDD expressed in nanometers, must be less than 500 nm. The second measure, as the volume-weighted percentage of fat greater than 5 microm or PFAT(5), must be less than 0.05%. These limits were first suggested in 2001 based on an analysis of 16 lipid injectable emulsions available worldwide. In 2004, the packaging of the innovator lipid emulsion product Intralipid was changed from conventional glass bottles to plastic containers in the U.S. A subsequent analysis of the emulsion in its new container showed it to be more coarse than its previous glass counterpart and now failed the PFAT(5) limit. In 2007, it was announced that Intralipid in plastic containers was reformulated to meet the pharmacopeial limits. To track the time course of its transition from a coarse to a fine dispersion, 31 lots of Intralipid with expiration dates spanning five years were investigated.

Globule-size distribution in injectable 20% lipid emulsions: Compliance with USP requirements.

PURPOSE: The compliance of injectable 20% lipid emulsions with the globule-size limits in chapter 729 of the U.S. Pharmacopeia (USP) was examined. METHODS: As established in chapter 729, dynamic light scattering was applied to determine mean droplet diameter (MDD), with an upper limit of 500 nm. Light obscuration was used to determine the size of fat globules found in the large-diameter tail, expressed as the volume-weighted percent fat exceeding 5 microm (PFAT(5)), with an upper limit of 0.05%. Compliance of seven different emulsions, six of which were stored in plastic bags, with USP limits was assessed. To avoid reaching coincidence limits during the application of method II from overly concentrated emulsion samples, a variable dilution scheme was used to optimize the globule-size measurements for each emulsion. One-way analysis of variance of globule-size distribution (GSD) data was conducted if any results of method I or II exceeded the respective upper limits. RESULTS: Most injectable lipid emulsions complied with limits established by USP chapter 729, with the exception of those of one manufacturer, which failed limits as proposed for to meet the PFAT(5) three of the emulsions tested. In contrast, all others studied (one packaged in glass and three packaged in plastic) met both criteria. CONCLUSION: Among seven injectable lipid emulsions tested for GSD, all met USP chapter 729 MDD requirements and three, all from the same manufacturer and packaged in plastic, did not meet PFAT(5) requirements.