Clinical Nutrition xxx (2014) 1e5
Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Original article
Parenteral nutrition admixtures for pediatric patients compounded with highly refined fish oil-based emulsion: Assessment of physicochemical stability M.L. Forchielli a, *, A. Bonoli c, I. Preite c, A. Stancari b, S. Maselli b, A.M. Guarguaglini b, I. Mignini b, M. Masi a,1, C. Puggioli b, G. Bersani b,1 a b c
Paediatrics, S. Orsola-Malpighi Medical School, Bologna, Italy Pharmacy Service, S. Orsola-Malpighi Hospital, Medical School, Bologna, Italy Civil, Environmental and Materials Engineering Department, University of Bologna, Italy
a r t i c l e i n f o
s u m m a r y
Article history: Received 28 May 2013 Accepted 27 December 2013
Fish oil-based emulsion is increasingly used in pediatric patients receiving Parenteral Nutrition (PN). However, its unique use in children on long-term PN is nutritionally debatable as some patients are better off with a mixture of long-chain (LCT) or long-chain þ medium-chain (LCT þ MCT) triglycerides along with Fish Oil (FO). Lipid emulsions are safely infused when particle diameter ranges between 0.4 and 1.0 micron (like chylomicra), according to European guidelines. No data exist on Fish Oil stability when added to other PN components typically present in pediatric formulations such as other lipids or micronutrients. Our goal is to evaluate the stability of a highly refined FO-emulsion in PN admixtures containing LCT or LCT þ MCT triglycerides and different calcium content. Stability studies were carried out on six PN admixtures having two levels of calcium concentration compounded with olive oil LCT þ FO, LCT þ MCT þ FO emulsion and pure FO alone, respectively. The analyses were performed immediately at time 0 (t ¼ 0) and 24, 48, 72, 96 (t ¼ 96) hours after compounding. Particle diameters were determined by Light Scattering-Reverse Fourier Optics Technique by means of a Laser Granulometer. Every sample was stored at 4 C and triple tested. Statistical significance was verified by f-test. In all admixtures, physicochemical stability did not change between t ¼ 0 and t ¼ 96 and particle diameters were in the expected range of 0.4e1.0 micron provided calcium concentration remained below 4.5 mmol/L. When calcium exceeded that level, 12% of particle diameters was larger than 1.0 micron and 2% exceeded 5.0 micron immediately after compounding. In particular, admixtures compounded with olive oil LCT þ FO emulsion or FO emulsion alone showed lower particle diameters compared to admixture with olive/soybean LCT alone, probably due to a different steric encumbrance of oleic acid and omega-3 fatty acid. In the PN admixtures tested, containing FO-emulsion alone or in combination with olive LCT or LCT þ MCT, the fat emulsion appears to be stable and safe for infusion when calcium concentration is maintained below 4.5 mmol/L. If calcium level exceeds 4.5 mmol/L, as often required in premature patients, it is advisable to infuse FO emulsion alone through a second intravenous line. Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.
Keywords: Omega-3 fatty acids Calcium concentration Stability study Laser diffraction technique
1. Introduction Fish oil-based emulsion is increasingly used in pediatric patients receiving Parenteral Nutrition (PN). However, its unique use in * Corresponding author. S. Orsola-Malpighi Medical School Bologna, Via Massarenti, 11, 40138 Bologna, Italy. E-mail address: [email protected] (M.L. Forchielli). 1 Retired.
children on long-term PN is nutritionally debatable as some patients are better off with a mixture of long-chain (LCT) or longchain þ medium-chain (LCT þ MCT) triglycerides along with Fish Oil (FO).1,2 Lipid emulsions are safely infused when particle diameter ranges between 0.4 and 1.0 micron(like chylomicra), according to European and Italian guidelines.3e6 No data exist on FO stability when added to other PN components typically present in pediatric formulations such as other lipids or micronutrients. As well established, All-in-One parenteral admixtures are complex oil/
0261-5614/$ e see front matter Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. http://dx.doi.org/10.1016/j.clnu.2013.12.011
Please cite this article in press as: Forchielli ML, et al., Parenteral nutrition admixtures for pediatric patients compounded with highly refined fish oil-based emulsion: Assessment of physicochemical stability, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2013.12.011
2
M.L. Forchielli et al. / Clinical Nutrition xxx (2014) 1e5
water lipid emulsions which require careful compounding and physicochemical stability assessment in order to ensure absolute sterility and no precipitates. The preparation of admixtures where fish oil (FO), which is rich in omega-3 polyunsaturated fatty acids (PUFAs), is combined with enriched lipid emulsion or long chain triglycerides (LCT) or long chain triglycerides (LCT) þ medium chain triglycerides (MCT), raises the stability issue, because omega3 are easily oxidized and can destabilize All-In-One admixtures in a short time, especially in the presence of high calcium concentration. Our goal is to evaluate the stability of a highly refined FOemulsion in PN admixtures containing LCT or LCT þ MCT triglycerides combined with different contents of calcium over the period of preparation, storage and clinical use. This is in order to ensure a safe infusion especially in pediatric patients. 2. Materials and methods 2.1. Admixtures Stability studies were carried out on twelve All-in-One pediatric admixtures having different calcium contents and lipid profiles. Other nutrients (glucose, amino acids, vitamins and trace elements) were variably combined to reproduce formulations which would typically cover the nutritional needs of children and neonates. Stability of all added nutrients, especially those related to vitamins, has been proven in a previous study.7 The selected lipid emulsions were olive/soybean LCT (ClinoleicÒ 20%, Baxter, Rome Italy 5000 mL), pure fish oil - based emulsion (OmegavenÒ 10%, Fresenius-Kabi, Ganz Austria 100 mL), and long chain triglycerides þ medium chain triglycerides (Lipofundin MCT 10% þ 10%Ò, Braun, Milan Italy 500 mL). These lipid emulsions were variably combined to make the following pairs: admixtures 1 and 2 with olive/soybean LCT þ FO, admixtures 3 and 4 with LCT þ MCT þ FO, and admixtures 5 and 6 with FO alone. Within each pair, the difference in the two formulations was the amount of calcium content. Tables 1and 2 show the different composition of industrial lipid emulsions and compounded admixtures, respectively. All-in-One admixtures were prepared into ethyl-vinyl acetate (EVA) plastic bags by the Parenteral Nutrition Centralized Pharmacy Service e S. Orsola-Malpighi University Hospital, Bologna, Italy through an automatic system (Siframix, Fresenius-Kabi, Ganz, Austria GmbH) in a clean room under positive pressure and vertical air flow filtered by HEPA absolute filters. Admixtures were properly stored at 4 C until samples were collected and analyzed at time 0 (t ¼ 0), 24, 48, 72 and 96 h after compounding to reproduce storage and infusion conditions. 2.2. Lipid particle dimension Lipid particle diameters were determined by means of Laser Particle Sizer Analysette 22 (Fritsch, Idar-Oberstein, Deutschland), which uses laser diffraction technique (Light scattering-Reverse Fourier Optics). This apparatus and the particle measurement technique have been described in previous studies.7e11 This technique evaluates particle size of lipid emulsions based on the degree of scattering of an incident light beam. This effect is inversely proportional to particle diameter: the smaller is the particle size, the wider is the angle of the light angle diffraction. This allows measurements of particles smaller than 0.1 mm. After setting granulometer at zero, a PN sample (5 ml) diluted by distilled water (15 ml) to reach sample/water ratio (1: 3 v/v) was introduced into the dispersion unit. The measuring range was set between 0.16 mm and 1160 mm. On average, samples were injected every 15e20 min to allow for proper cleaning of the measuring cell
Table 1 Composition of selected industrial lipid emulsions. ClinOleicÒ 20% OmegavenÒ LipofundinÒ MCT 10% þ 10% B.Braun, Baxter, Rome, 10% Fresenius-Kabi, Milan, Italy Italy Ganz, Austria GmbH 100.0 g/L 40.0 g/L Soybean fractionated lipids Purified olive oil e 160.0 g/L MCT (from 100.0 g/L e coconut oil) Fish oil e e Egg yolk micronized phospholipids 12.0 g/L 12.0 g/L Phosphate 13.5 mmol/L 13.5 mmol/L Glycerol 25.0 g/L 22.5 g/L Sodium oleate 4 mmol/L 4 mmol/L Fatty acid composition: (% of total lipids): LCT LCT 50% LCT 100% Linoleic acid 27.0 g 18.5 g a-linolenic acid 4.0 g 2.0 g Oleic acid 12.0 g 59.5 g Palmitic acid 5.0 g 13.5 g Stearic acid 2.0 g 2.9 g Other LCT e 3.6 g MCT MCT 50% e Caprilic acid 27.0 g e Capric acid 21.0 g e Caproic acid 1.0 g e Lauric acid 1.0 g e EPA e e DHA e Other omega-3 e PUFAs (w/w%) 31% 20.5% Tocopherol amount 240.0 mg/L 70.0 mg/L Phytomenadione traces 15e20 m/L Osmolarity 380 mOsm/L 380 mOsm/L pH 6.6e8.5 7e8
e
e e 100 g/L 12.0 g/L 13.5 mmol/L 25.0 g/L 5 micron not exceeding the proportion of 0.05%) according to the United States Pharmacopeia guidelines in intravenous emulsions.12,13 Our results reached a good level of repeatability as shown by the very narrow standard deviations in the triple measurement of particle diameters. In addition, the light scattering technique had the advantage of requiring a low sample dilution, which is essential to define lipid emulsion stability, because an excessive sample dilution may mask emulsion flocculation phenomena. Finally, our stability results were homogeneous and, consequently, comparable with other formulations previously evaluated by the same laser diffraction apparatus.7 This study identified a calcium cut off above which lipid emulsions may compromise admixture stability. In the literature, no other report seems to offer similar detailed information to be applied in common practice. Télessy et al. showed droplet size within the expected range (0.2e0.6 micron) in different solutions with and without calcium during the first 24 h of infusion.14 However, he could not be more specific when evaluating the supernatant phase in terms of over 5 micron droplets quantification. In an attempt to place our admixtures in context to the ESPEN guidelines for Paediatric PN, we computed the ratio of calcium to phosphorus for which ESPEN’s premature, neonatal and pediatric recommended range is 1e1.7:1.15 Only half of our admixtures fell within this range with one above and five below presumably to meet the requirements of some of our severe patients. Interestingly, out of the five below ratio, four belonged to the stable group with calcium below 4.5 mmol/L. No comments can be made whether this aspect would have an impact on calcium and phosphorus precipitation and lipid droplet surface charge. The smaller particle diameters found in the FO and olive/soybean LCT þ FO based admixtures compared to the olive/soybean LCT admixtures alone led us to further inquire about possible options. Our first hypothesis has to do with a different steric encumbrance occurring to oleic acid, which seems to fold back on itself in the presence of omega-3 fatty acids, which, in turn, are less viscous. The second hypothesis follows the assumption that monounsaturated oleic oils can offer an optimal compromise
5
between oxidative stability and low temperature properties through hydrogenation conversion of unstable unsaturated fatty acid chains to stable saturated molecules. This effect has been seen in the oxidative stabilities of biodiesel after a reduction in the unsaturation of fatty acid chains.15,16 In conclusion, this study’s results confirmed the chemical and so therapeutic safety of our 12 admixtures in which the PN lipid emulsions remained stable for four days after compounding. These results may not be extended to other PN admixtures. Therefore further research is warranted to safely act in unstable patients and neonates, who require higher calcium needs and constant variation in nutrients. Acknowledgments A special acknowledgment to Celso Vescogni - Civil, Environmental and Materials Engineering Department - University of Bologna - Italy, for his valuable collaboration in carrying out PN admixture analyses. References [1]. The British Nutrition Foundation, Recommendations for intakes of unsaturated fatty acids, Ed. Chapman & Hall, 1992;152e193. [2]. Turville B. Pediatric patients with liver cholestasis due to parenteral nutrition-associated liver disease: are omega-3s the answer? Top Nutrition 2011;26:138e46. [3]. Stancari A, Raitano A. Analisi di stabilità delle miscele parenterali complete (All-In-One).Boll S.I.F.O. 1996;42:28e44. [4]. Linee guida SINPE per la Nutrizione Artificiale Ospedaliera 2002, RINPE Anno 20, S5: Aggiornamento ottobre 2003. [5]. ESPEN, guidelines for enteral and parenteral nutrition 2009;28:359e480. [6]. Farmacopea Ufficiale Italiana. Norme di Buona preparazione dei Medicinali. XII ed.; 2008. pp. 1417e26. [7]. Sforzini A, Bersani G, Stancari A, Grossi G, Bonoli A, Ceschel GC. Analysis of allin-one parenteral nutrition admixtures by liquid chromatography and laser diffraction: study of stability. J Pharm Biomed Anal 2001;24:1099e109. [8]. James PM, Syvitski M. Principles, methods and applications of particle size analysis. Cambridge University Press; 1991. pp. 1e17. [9]. Washingtin C. In: Particle size analysis in pharmaceutics and other industries. Hellis Horwood Limited; 1992. } rst P, Sthele P. Safety and efficacy of a new parenteral [10]. Mertes N, Grimm H, Fu lipid emulsion (SMOFlipid) in surgical patients: a randomized, double-blind, multicenter study. Ann Nutr Metab 2006;50:253e9. [11]. Xu R. Particle characterization: light scattering methods. Kluwer Academic Publishers; 2002. [12]. USP general chapters, globule size distributions in lipid injectable emulsions. USP31/NF26, 729 (2008) 285e287. [13]. Discroll DF, Etzler F, Barber TA, Nehne J, Niemann W, Bistrian BR. Physicochemical assessments of parenteral lipid emulsions: light obscuration versus laser diffraction. Int J Pharm 2001;219:21e37. [14]. Télessy IG, Balogh J, Szabo B, Csempesz F, Zelko R. Kinetic stability of all-inone parenteral nutrition admixtures in the presence of high dose Ca2þ additive under clinical application circumstances. Nutr J 2012;11:32. http:// dx.doi.org/10.1186/1475-2891-11-32. [15]. Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. Guidelines on pediatric parenteral nutrition of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Ped Gastroenterol Nutr 2005;41:S39e46. [16]. http://www.worldenergy.org/documents/annex4biofuelappscanada.pdf, [last access on 17.04.13].
Please cite this article in press as: Forchielli ML, et al., Parenteral nutrition admixtures for pediatric patients compounded with highly refined fish oil-based emulsion: Assessment of physicochemical stability, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2013.12.011
Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Original article
Parenteral nutrition admixtures for pediatric patients compounded with highly refined fish oil-based emulsion: Assessment of physicochemical stability M.L. Forchielli a, *, A. Bonoli c, I. Preite c, A. Stancari b, S. Maselli b, A.M. Guarguaglini b, I. Mignini b, M. Masi a,1, C. Puggioli b, G. Bersani b,1 a b c
Paediatrics, S. Orsola-Malpighi Medical School, Bologna, Italy Pharmacy Service, S. Orsola-Malpighi Hospital, Medical School, Bologna, Italy Civil, Environmental and Materials Engineering Department, University of Bologna, Italy
a r t i c l e i n f o
s u m m a r y
Article history: Received 28 May 2013 Accepted 27 December 2013
Fish oil-based emulsion is increasingly used in pediatric patients receiving Parenteral Nutrition (PN). However, its unique use in children on long-term PN is nutritionally debatable as some patients are better off with a mixture of long-chain (LCT) or long-chain þ medium-chain (LCT þ MCT) triglycerides along with Fish Oil (FO). Lipid emulsions are safely infused when particle diameter ranges between 0.4 and 1.0 micron (like chylomicra), according to European guidelines. No data exist on Fish Oil stability when added to other PN components typically present in pediatric formulations such as other lipids or micronutrients. Our goal is to evaluate the stability of a highly refined FO-emulsion in PN admixtures containing LCT or LCT þ MCT triglycerides and different calcium content. Stability studies were carried out on six PN admixtures having two levels of calcium concentration compounded with olive oil LCT þ FO, LCT þ MCT þ FO emulsion and pure FO alone, respectively. The analyses were performed immediately at time 0 (t ¼ 0) and 24, 48, 72, 96 (t ¼ 96) hours after compounding. Particle diameters were determined by Light Scattering-Reverse Fourier Optics Technique by means of a Laser Granulometer. Every sample was stored at 4 C and triple tested. Statistical significance was verified by f-test. In all admixtures, physicochemical stability did not change between t ¼ 0 and t ¼ 96 and particle diameters were in the expected range of 0.4e1.0 micron provided calcium concentration remained below 4.5 mmol/L. When calcium exceeded that level, 12% of particle diameters was larger than 1.0 micron and 2% exceeded 5.0 micron immediately after compounding. In particular, admixtures compounded with olive oil LCT þ FO emulsion or FO emulsion alone showed lower particle diameters compared to admixture with olive/soybean LCT alone, probably due to a different steric encumbrance of oleic acid and omega-3 fatty acid. In the PN admixtures tested, containing FO-emulsion alone or in combination with olive LCT or LCT þ MCT, the fat emulsion appears to be stable and safe for infusion when calcium concentration is maintained below 4.5 mmol/L. If calcium level exceeds 4.5 mmol/L, as often required in premature patients, it is advisable to infuse FO emulsion alone through a second intravenous line. Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.
Keywords: Omega-3 fatty acids Calcium concentration Stability study Laser diffraction technique
1. Introduction Fish oil-based emulsion is increasingly used in pediatric patients receiving Parenteral Nutrition (PN). However, its unique use in * Corresponding author. S. Orsola-Malpighi Medical School Bologna, Via Massarenti, 11, 40138 Bologna, Italy. E-mail address: [email protected] (M.L. Forchielli). 1 Retired.
children on long-term PN is nutritionally debatable as some patients are better off with a mixture of long-chain (LCT) or longchain þ medium-chain (LCT þ MCT) triglycerides along with Fish Oil (FO).1,2 Lipid emulsions are safely infused when particle diameter ranges between 0.4 and 1.0 micron(like chylomicra), according to European and Italian guidelines.3e6 No data exist on FO stability when added to other PN components typically present in pediatric formulations such as other lipids or micronutrients. As well established, All-in-One parenteral admixtures are complex oil/
0261-5614/$ e see front matter Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. http://dx.doi.org/10.1016/j.clnu.2013.12.011
Please cite this article in press as: Forchielli ML, et al., Parenteral nutrition admixtures for pediatric patients compounded with highly refined fish oil-based emulsion: Assessment of physicochemical stability, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2013.12.011
2
M.L. Forchielli et al. / Clinical Nutrition xxx (2014) 1e5
water lipid emulsions which require careful compounding and physicochemical stability assessment in order to ensure absolute sterility and no precipitates. The preparation of admixtures where fish oil (FO), which is rich in omega-3 polyunsaturated fatty acids (PUFAs), is combined with enriched lipid emulsion or long chain triglycerides (LCT) or long chain triglycerides (LCT) þ medium chain triglycerides (MCT), raises the stability issue, because omega3 are easily oxidized and can destabilize All-In-One admixtures in a short time, especially in the presence of high calcium concentration. Our goal is to evaluate the stability of a highly refined FOemulsion in PN admixtures containing LCT or LCT þ MCT triglycerides combined with different contents of calcium over the period of preparation, storage and clinical use. This is in order to ensure a safe infusion especially in pediatric patients. 2. Materials and methods 2.1. Admixtures Stability studies were carried out on twelve All-in-One pediatric admixtures having different calcium contents and lipid profiles. Other nutrients (glucose, amino acids, vitamins and trace elements) were variably combined to reproduce formulations which would typically cover the nutritional needs of children and neonates. Stability of all added nutrients, especially those related to vitamins, has been proven in a previous study.7 The selected lipid emulsions were olive/soybean LCT (ClinoleicÒ 20%, Baxter, Rome Italy 5000 mL), pure fish oil - based emulsion (OmegavenÒ 10%, Fresenius-Kabi, Ganz Austria 100 mL), and long chain triglycerides þ medium chain triglycerides (Lipofundin MCT 10% þ 10%Ò, Braun, Milan Italy 500 mL). These lipid emulsions were variably combined to make the following pairs: admixtures 1 and 2 with olive/soybean LCT þ FO, admixtures 3 and 4 with LCT þ MCT þ FO, and admixtures 5 and 6 with FO alone. Within each pair, the difference in the two formulations was the amount of calcium content. Tables 1and 2 show the different composition of industrial lipid emulsions and compounded admixtures, respectively. All-in-One admixtures were prepared into ethyl-vinyl acetate (EVA) plastic bags by the Parenteral Nutrition Centralized Pharmacy Service e S. Orsola-Malpighi University Hospital, Bologna, Italy through an automatic system (Siframix, Fresenius-Kabi, Ganz, Austria GmbH) in a clean room under positive pressure and vertical air flow filtered by HEPA absolute filters. Admixtures were properly stored at 4 C until samples were collected and analyzed at time 0 (t ¼ 0), 24, 48, 72 and 96 h after compounding to reproduce storage and infusion conditions. 2.2. Lipid particle dimension Lipid particle diameters were determined by means of Laser Particle Sizer Analysette 22 (Fritsch, Idar-Oberstein, Deutschland), which uses laser diffraction technique (Light scattering-Reverse Fourier Optics). This apparatus and the particle measurement technique have been described in previous studies.7e11 This technique evaluates particle size of lipid emulsions based on the degree of scattering of an incident light beam. This effect is inversely proportional to particle diameter: the smaller is the particle size, the wider is the angle of the light angle diffraction. This allows measurements of particles smaller than 0.1 mm. After setting granulometer at zero, a PN sample (5 ml) diluted by distilled water (15 ml) to reach sample/water ratio (1: 3 v/v) was introduced into the dispersion unit. The measuring range was set between 0.16 mm and 1160 mm. On average, samples were injected every 15e20 min to allow for proper cleaning of the measuring cell
Table 1 Composition of selected industrial lipid emulsions. ClinOleicÒ 20% OmegavenÒ LipofundinÒ MCT 10% þ 10% B.Braun, Baxter, Rome, 10% Fresenius-Kabi, Milan, Italy Italy Ganz, Austria GmbH 100.0 g/L 40.0 g/L Soybean fractionated lipids Purified olive oil e 160.0 g/L MCT (from 100.0 g/L e coconut oil) Fish oil e e Egg yolk micronized phospholipids 12.0 g/L 12.0 g/L Phosphate 13.5 mmol/L 13.5 mmol/L Glycerol 25.0 g/L 22.5 g/L Sodium oleate 4 mmol/L 4 mmol/L Fatty acid composition: (% of total lipids): LCT LCT 50% LCT 100% Linoleic acid 27.0 g 18.5 g a-linolenic acid 4.0 g 2.0 g Oleic acid 12.0 g 59.5 g Palmitic acid 5.0 g 13.5 g Stearic acid 2.0 g 2.9 g Other LCT e 3.6 g MCT MCT 50% e Caprilic acid 27.0 g e Capric acid 21.0 g e Caproic acid 1.0 g e Lauric acid 1.0 g e EPA e e DHA e Other omega-3 e PUFAs (w/w%) 31% 20.5% Tocopherol amount 240.0 mg/L 70.0 mg/L Phytomenadione traces 15e20 m/L Osmolarity 380 mOsm/L 380 mOsm/L pH 6.6e8.5 7e8
e
e e 100 g/L 12.0 g/L 13.5 mmol/L 25.0 g/L 5 micron not exceeding the proportion of 0.05%) according to the United States Pharmacopeia guidelines in intravenous emulsions.12,13 Our results reached a good level of repeatability as shown by the very narrow standard deviations in the triple measurement of particle diameters. In addition, the light scattering technique had the advantage of requiring a low sample dilution, which is essential to define lipid emulsion stability, because an excessive sample dilution may mask emulsion flocculation phenomena. Finally, our stability results were homogeneous and, consequently, comparable with other formulations previously evaluated by the same laser diffraction apparatus.7 This study identified a calcium cut off above which lipid emulsions may compromise admixture stability. In the literature, no other report seems to offer similar detailed information to be applied in common practice. Télessy et al. showed droplet size within the expected range (0.2e0.6 micron) in different solutions with and without calcium during the first 24 h of infusion.14 However, he could not be more specific when evaluating the supernatant phase in terms of over 5 micron droplets quantification. In an attempt to place our admixtures in context to the ESPEN guidelines for Paediatric PN, we computed the ratio of calcium to phosphorus for which ESPEN’s premature, neonatal and pediatric recommended range is 1e1.7:1.15 Only half of our admixtures fell within this range with one above and five below presumably to meet the requirements of some of our severe patients. Interestingly, out of the five below ratio, four belonged to the stable group with calcium below 4.5 mmol/L. No comments can be made whether this aspect would have an impact on calcium and phosphorus precipitation and lipid droplet surface charge. The smaller particle diameters found in the FO and olive/soybean LCT þ FO based admixtures compared to the olive/soybean LCT admixtures alone led us to further inquire about possible options. Our first hypothesis has to do with a different steric encumbrance occurring to oleic acid, which seems to fold back on itself in the presence of omega-3 fatty acids, which, in turn, are less viscous. The second hypothesis follows the assumption that monounsaturated oleic oils can offer an optimal compromise
5
between oxidative stability and low temperature properties through hydrogenation conversion of unstable unsaturated fatty acid chains to stable saturated molecules. This effect has been seen in the oxidative stabilities of biodiesel after a reduction in the unsaturation of fatty acid chains.15,16 In conclusion, this study’s results confirmed the chemical and so therapeutic safety of our 12 admixtures in which the PN lipid emulsions remained stable for four days after compounding. These results may not be extended to other PN admixtures. Therefore further research is warranted to safely act in unstable patients and neonates, who require higher calcium needs and constant variation in nutrients. Acknowledgments A special acknowledgment to Celso Vescogni - Civil, Environmental and Materials Engineering Department - University of Bologna - Italy, for his valuable collaboration in carrying out PN admixture analyses. References [1]. The British Nutrition Foundation, Recommendations for intakes of unsaturated fatty acids, Ed. Chapman & Hall, 1992;152e193. [2]. Turville B. Pediatric patients with liver cholestasis due to parenteral nutrition-associated liver disease: are omega-3s the answer? Top Nutrition 2011;26:138e46. [3]. Stancari A, Raitano A. Analisi di stabilità delle miscele parenterali complete (All-In-One).Boll S.I.F.O. 1996;42:28e44. [4]. Linee guida SINPE per la Nutrizione Artificiale Ospedaliera 2002, RINPE Anno 20, S5: Aggiornamento ottobre 2003. [5]. ESPEN, guidelines for enteral and parenteral nutrition 2009;28:359e480. [6]. Farmacopea Ufficiale Italiana. Norme di Buona preparazione dei Medicinali. XII ed.; 2008. pp. 1417e26. [7]. Sforzini A, Bersani G, Stancari A, Grossi G, Bonoli A, Ceschel GC. Analysis of allin-one parenteral nutrition admixtures by liquid chromatography and laser diffraction: study of stability. J Pharm Biomed Anal 2001;24:1099e109. [8]. James PM, Syvitski M. Principles, methods and applications of particle size analysis. Cambridge University Press; 1991. pp. 1e17. [9]. Washingtin C. In: Particle size analysis in pharmaceutics and other industries. Hellis Horwood Limited; 1992. } rst P, Sthele P. Safety and efficacy of a new parenteral [10]. Mertes N, Grimm H, Fu lipid emulsion (SMOFlipid) in surgical patients: a randomized, double-blind, multicenter study. Ann Nutr Metab 2006;50:253e9. [11]. Xu R. Particle characterization: light scattering methods. Kluwer Academic Publishers; 2002. [12]. USP general chapters, globule size distributions in lipid injectable emulsions. USP31/NF26, 729 (2008) 285e287. [13]. Discroll DF, Etzler F, Barber TA, Nehne J, Niemann W, Bistrian BR. Physicochemical assessments of parenteral lipid emulsions: light obscuration versus laser diffraction. Int J Pharm 2001;219:21e37. [14]. Télessy IG, Balogh J, Szabo B, Csempesz F, Zelko R. Kinetic stability of all-inone parenteral nutrition admixtures in the presence of high dose Ca2þ additive under clinical application circumstances. Nutr J 2012;11:32. http:// dx.doi.org/10.1186/1475-2891-11-32. [15]. Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. Guidelines on pediatric parenteral nutrition of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Ped Gastroenterol Nutr 2005;41:S39e46. [16]. http://www.worldenergy.org/documents/annex4biofuelappscanada.pdf, [last access on 17.04.13].
Please cite this article in press as: Forchielli ML, et al., Parenteral nutrition admixtures for pediatric patients compounded with highly refined fish oil-based emulsion: Assessment of physicochemical stability, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2013.12.011
