Phytosterolaemia associated with parenteral nutrition administration in adult patients.

Vegetable lipid emulsions (LE) contain non-declared phytosterols (PS). We aimed to determine PS content depending on the brand and LE batch, and in adult hospitalised patients treated with parenteral nutrition (PN), to establish the association between plasma and administered PS. Part I was the LE study: totals and fractions of PS in three to four non-consecutive batches from six LE were analysed. Part II was the patient study: patients with at least 7 previous days of PN with 0·8 g/kg per d of an olive/soyabean (O/S) LE were randomised (day 0) 1:1 to O/S or 100 % fish oil (FO) at a dose of 0·4 g/kg per d for 7 d (day 7). Plasma PS, its fractions, total cholesterol on days 0 and 7, their clearance and their association with PS administered by LE were studied. In part I, LE study: differences were found in the total PS, their fractions and cholesterol among different LE brands and batches. Exclusive soyabean LE had the highest content of PS (422·36 (sd 130·46) µg/ml). In part II, patient study: nineteen patients were included. In the O/S group, PS levels were maintained (1·11 (sd 6·98) µg/ml) from day 0 to 7, while in the FO group, significant decreases were seen in total PS (-6·21 (sd 4·73) µg/ml) and their fractions, except for campesterol and stigmasterol. Plasma PS on day 7 were significantly associated with PS administered (R2 0·443). PS content in different LE brands had great variability. PS administered during PN resulted in accumulation and could be prevented with the exclusive administration of FO LE.

Oxylipins and Free Fatty Acids in Parenteral Lipid Emulsions Currently Used in Preterm Infant Care: An In Vitro Study.

Lipid emulsions used to support nutrition in preterm infants contain long-chain polyunsaturated fatty acids (LCPUFAs) as a source of essential fatty acids; these LCPUFAs and their parent polyunsaturated fatty acid (PUFA) can be oxidized by a variety of mechanisms to bioactive molecules called oxylipins, which are signaling molecules that initiate and/or resolve inflammation. The aim of this study was to explore levels of free LCPUFA and their related oxylipins in 3 commercially available lipid emulsions (Intralipid, SMOFlipid, and ClinOleic) using ultra high-performance liquid chromatography mass spectroscopy. Free LCPUFA were detected in all lipid emulsions tested. Seven, 8, and 9 different oxylipin compounds were detected in the 3 emulsions, respectively. The oxylipins detected were mainly derived from omega-6 PUFAs; these included 13-hydroxyoctadecadienoic acid from linoleic acid and 5-hydroxyeicosatetraenoic acid derived from arachidonic acid. It may be clinically important to know that oxylipins exist in lipid emulsions and to evaluate their potential effects on preterm infants.

A HPLC method to monitor the occurrence of lipid peroxidation in intravenous lipid emulsions used in parenteral nutrition using in-line UV and charged aerosol detection.

Parenteral Nutrition (PN) provides life sustaining support where gastrointestinal nutrition is inadequate due to disease or prematurity. Intravenous lipid emulsions (IVLEs) form a staple part of PN. Whilst the physical stability of IVLE's is relatively well known and quantified, chemical stability is an area where little testing has occurred. We report a new sensitive method for the monitoring of selected triglycerides present within two IVLEs and the detection and quantification of the peroxidation product 4-hydroxynonenal (HNE) using HPLC with in-line UV and charged aerosol detection (CAD). IVLEs used included the soy-bean oil based emulsion Intralipid® 20% and SMOFlipid® 20% (Fresenius Kabi UK), based on soy-bean, olive, fish oil and medium chain triglycerides. Assay validation gave R2 values of ≥0.99 for all selected triglyceride peaks and 4-hydroxynonenal. Inter and intra-day repeatability gave RSD values < 7.2% for CAD detection, achieving a precise and repeatable method. HNE was confirmed through internal standardisation of the HPLC method. Selected triglycerides were identified using ESI-MS with MicroTOF. This novel method permits the chemical stability of IVLEs to be quantified and monitored in respect to lipid peroxidation during storage prior to delivery to the patient, ensuring the optimal safety of IVLEs in a clinical setting.

Determinación de fitoesteroles en emulsiones lipídicas para nutrición parenteral / Phytosterol determination in lipid emulsions for parenteral nutrition

Objetivo: La presencia de fitoesteroles en emulsiones lipídicas de origen vegetal se ha relacionado con la aparición de alteraciones de los parámetros de la función hepática. El objetivo es determinar la presencia de fitoesteroles en las emulsiones registradas en el mercado farmacéutico. Método: Se analizaron tres-cuatro lotes no consecutivos de seis marcas distintas de emulsiones lipídicas (Clinoleic(R), Intralipid(R), Lipofundina(R), Lipoplus(R), Omegaven(R) y Smoflipid(R)) y las diferencias en contenido de fitoesteroles totales entre marcas y entre lotes se estudiaron estadísticamente (ANOVA de un factor, aproximación no paramétrica de Kruskal-Wallis y análisis post hoc Scheffé; p < 0,05). Resultados: Se encontró ausencia de fitoesteroles en el preparado Omegaven(R) con aceite de pescado. El contenido más alto de fitoesteroles (422,4 ± 130,5 µg/mL) coincidió con el porcentaje más alto de aceite de soja (Intralipid(R)). En el resto de las emulsiones se detectaron concentraciones de fitoesteroles entre 120 y 210 µg/mL, relacionadas con el contenido de aceite de soja. Se observaron diferencias estadísticamente significativas entre todas las marcas de emulsiones lipídicas (F = 42,97; p = 0,000) y entre lotes no consecutivos. Clinolenic(R) (F = 23,59; p = 0,000); Intralipid(R) (F = 978,25; p = 0,000); Lipofundina(R) TCL/TCM (F = 5,43; p = 0,045); Lipoplus(R) (F = 123,53; p = 0,000),; y Smoflipid(R) (16,78; p = 0,000). Excepto en el caso de la Lipofundina(R) TCL/TCM las diferencias entre lotes fueron marcadas. Conclusiones: Las emulsiones lipídicas registradas en el mercado farmacéutico español contienen cantidades variables de fitoesteroles en función de la marca comercial y el lote. La determinación del contenido de fitoesteroles, actualmente no declarados, permitiría desarrollar estrategias para prevenir o tratar la aparición de estas alteraciones

Objective: The presence of phytosterols in vegetal lipid emulsions has been associated with alterations of liver function tests. Determination of phytosterols content, currently undeclared, would allow the development of strategies to prevent or treat these alterations. Method: 3-4 non-consecutive batches of 6 lipid emulsions from different providers (Clinoleic(TM), Intralipid(TM), Lipofundina(TM), Lipoplus(TM), Omegaven(TM) and Smoflipid(TM)) were analyzed. Differences in total phytosterol assay between providers and batches were statistically studied by a one-way ANOVA and Kruskal-Wallis non-parametric approximation and post hoc Scheffé test (p < 0.05). Results: The absence of phytosterols was confirmed in Omegaven(TM), emulsion based on fish oil. The highest assay of phytosterols (422.4 ± 130.5 µg/mL) has been related with the highest percentage of soya bean oil in Intralipid. In the remaining emulsions, concentrations were from 120 to 210 µg/mL related to the percentage of soya bean oil. Statistically significant differences of phytosterol content in lipid emulsions were observed among different providers (F = 23.59; p = 0.000) as well as among non-consecutive batches. Clinolenic(TM) (F = 23.59; p = 0.000), Intralipid(TM) (F = 978.25; p = 0.000), Lipofundina(TM) TCL/TCM (F = 5.43; p = 0.045), Lipoplus(TM) (F = 123.53; p = 0.000) and Smoflipid(TM) (16.78; p = 0.000). Except for Lipofundina(TM) TCL/TCM, the differences between batches were marked. Conclusions: Lipid emulsions, registered on Spanish pharmaceutical market, contain variable quantities of phytosterols dependent on commercial brand and batch

Phytosterol determination in lipid emulsions for parenteral nutrition.

OBJECTIVE: The presence of phytosterols in vegetal lipid emulsions has been  associated with alterations of liver function tests. Determination of phytosterols  content, currently undeclared, would allow the development of strategies to  prevent or treat these alterations. METHOD: 3-4 non-consecutive batches of 6 lipid emulsions from different providers (Clinoleic, Intralipid, Lipofundina, Lipoplus, Omegaven and Smoflipid) were analyzed. Differences in total phytosterol assay between providers and batches were statistically studied by a one-way ANOVA and Kruskal-Wallis non-parametric approximation and post hoc Scheffé test (p < 0.05)Results: The absence of phytosterols was confirmed in Omegaven, emulsion  based on fish oil. The highest assay of phytosterols (422.4 ± 130.5 µg/mL) has  been related with the highest percentage of soya bean oil in Intralipid. In the  remaining emulsions, concentrations were from 120 to 210 µg/mL related to the  percentage of soya bean oil. Statistically significant differences of phytosterol  content in lipid emulsions were observed among different providers (F = 23.59;  p = 0.000) as well as among non-consecutive batches. Clinolenic (F = 23.59; p  = 0.000), Intralipid (F = 978.25; p = 0.000), Lipofundina TCL/TCM (F = 5.43; p  = 0.045), Lipoplus (F = 123.53; p = 0.000) and Smoflipid (16.78; p = 0.000).  Except for Lipofundina TCL/TCM, the differences between batches were marked. CONCLUSIONS: Lipid emulsions, registered on Spanish pharmaceutical market,  contain variable quantities of phytosterols dependent on commercial brand and  batch.

Objetivo: La presencia de fitoesteroles en emulsiones lipídicas de origen vegetal se ha relacionado con la aparición de alteraciones de los parámetros de la  función hepática. El objetivo es determinar la presencia de fitoesteroles en las  emulsiones registradas en el mercado farmacéutico.Método: Se analizaron tres-cuatro lotes no consecutivos de seis marcas  distintas de emulsiones lipídicas (Clinoleic®, Intralipid®, Lipofundina®,  Lipoplus®, Omegaven® y Smoflipid®) y las diferencias en contenido de  fitoesteroles totales entre marcas y entre lotes se estudiaron estadísticamente  (ANOVA de un factor, aproximación no paramétrica de Kruskal-Wallis y análisis  post hoc Scheffé; p < 0,05).Resultados: Se encontró ausencia de fitoesteroles en el preparado Omegaven® con aceite de pescado. El contenido más alto de fitoesteroles (422,4 ± 130,5  µg/mL) coincidió con el porcentaje más alto de aceite de soja (Intralipid®). En el resto de las emulsiones se detectaron concentraciones de fitoesteroles entre 120  y 210 µg/mL, relacionadas con el contenido de aceite de soja. Se  observaron diferencias estadísticamente significativas entre todas las marcas de  emulsiones lipídicas (F = 42,97; p = 0,000) y entre lotes no consecutivos.  Clinolenic® (F = 23,59; p = 0,000); Intralipid® (F = 978,25; p = 0,000);  Lipofundina® TCL/TCM (F = 5,43; p = 0,045); Lipoplus ® (F = 123,53; p =  0,000),; y Smoflipid® (16,78; p = 0,000). Excepto en el caso de la  Lipofundina® TCL/TCM las diferencias entre lotes fueron marcadas.Conclusiones: Las emulsiones lipídicas registradas en el mercado farmacéutico español contienen cantidades variables de fitoesteroles en función  e la marca comercial y el lote. La determinación del contenido de fitoesteroles, actualmente no declarados, permitiría desarrollar estrategias para prevenir o tratar la aparición de estas alteraciones.

[Fat emulsion tolerance in preterm infants of different gestational ages in the early stage after birth].

OBJECTIVE: To investigate the fat emulsion tolerance in preterm infants of different gestational ages in the early stage after birth. METHODS: A total of 98 preterm infants were enrolled and divided into extremely preterm infant group (n=17), early preterm infant group (n=48), and moderate-to-late preterm infant group (n=33). According to the dose of fat emulsion, they were further divided into low- and high-dose subgroups. The umbilical cord blood and dried blood filter papers within 3 days after birth were collected. Tandem mass spectrometry was used to measure the content of short-, medium-, and long-chain acylcarnitines. RESULTS: The extremely preterm infant and early preterm infant groups had a significantly lower content of long-chain acylcarnitines in the umbilical cord blood and dried blood filter papers within 3 days after birth than the moderate-to-late preterm infant group (P<0.05), and the content was positively correlated with gestational age (P<0.01). On the second day after birth, the low-dose fat emulsion subgroup had a significantly higher content of short-, medium-, and long-chain acylcarnitines than the high-dose fat emulsion subgroup among the extremely preterm infants (P<0.05). In the early preterm infant and moderate-to-late preterm infant groups, there were no significant differences in the content of short-, medium-, and long-chain acylcarnitines between the low- and high-dose fat emulsion subgroups within 3 days after birth. CONCLUSIONS: Compared with moderate-to-late preterm infants, extremely preterm infants and early preterm infants have a lower capacity to metabolize long-chain fatty acids within 3 days after birth. Early preterm infants and moderate-to-late preterm infants may tolerate high-dose fat emulsion in the early stage after birth, but extremely preterm infants may have an insufficient capacity to metabolize high-dose fat emulsion.

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.

An Institutional Change in Continuous Renal Replacement Therapy.

BACKGROUND: Critically ill patients with acute kidney injury may require parenteral nutrition (PN) and continuous renal replacement therapy (CRRT). Introduction of a phosphate-free premixed renal replacement fluid without system-wide education in May 2011 resulted in increased incidence of hypophosphatemia, necessitating change in practice. Changes included (1) maximizing phosphate in PN, (2) modifying the CRRT order set, and (3) developing a CRRT competency evaluation for nutrition support team members. This study evaluates the effect of these changes on the incidence of hypophosphatemia. METHODS: Phosphate levels and predicated probability of hypophosphatemia were evaluated for patients receiving PN and CRRT over 3 time periods: prior to implementing the changes (preimplementation), during change implementation (intermediate), and following implementation (postimplementation). Hypophosphatemia was defined as a serum phosphate level <2.5 mg/dL. Generalized linear mixed models were applied for statistical analysis. RESULTS: The retrospective study includes 336 measures from 49 patients. Patients in the intermediate and postimplementation periods were not significantly different from each other and had significantly higher mean phosphate levels than patients in the preimplementation period ( P < .0001). They were also less likely to develop hypophosphatemia compared with preimplementation patients (intermediate: odds ratio [OR], 0.07; 95% confidence interval [CI], 0.03-0.18, P < .0001; postimplementation: OR, 0.09; 95% CI, 0.03-0.27, P < .0001). CONCLUSIONS: Modifications in phosphate dosing together with CRRT education reduced the incidence of hypophosphatemia in PN patients receiving CRRT. Communication of significant changes in clinical care should be shared with all services prior to implementation. Communication and planning between services caring for complex patients are necessary to prevent systems-based problems.

Development of a validated LC-APCI-MS/MS method to study the plasma and tumor distribution of CHO-PTX intravenous lipid emulsion.

Conjugation of a cholesterol moiety to active compounds for cancer treatment or diagnosis is an attractive approach for increasing lipophilicity and improving loading into lipid carriers. We developed a highly sensitive and specific liquid chromatography atmospheric-pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS) analytical method to investigate the in vivo plasma and tumor distribution characteristic of a cholesterol-paclitaxel conjugate (CHO-PTX) in nude mice with MDA-MB-231 human breast cancer xenografts. The samples were analyzed in positive ion, multiple reaction monitoring mode. The plasma and tumor tissue samples were processed by liquid-liquid extraction with methyl tert-butyl ether (MTBE). Docetaxel was used as the internal standard (IS) for sample processing and analysis. MS/MS detection was carried out by monitoring the transitions of m/z 1266.7→369.4 and 330.3 for CHO-PTX, and m/z 808.7→226.4 and 509.1 for IS. The calibration curves were linear over 100-25,000 ng/mL in mouse plasma and tumor homogenate samples. The limit of quantitation of CHO-PTX was 100 ng/mL in both matrices. The intra-day and inter-day precisions were less than 15%, and the accuracy was between -8.0% and 8.6% for both matrices. The developed method was successfully applied to measure CHO-PTX levels in plasma and tumor tissues in nude mice. The mean tumor concentrations in mice tumor tissues after intravenous administration of CHO-PTX emulsion at a dose equivalent to 20 mg/kg paclitaxel were 2022±630 ng/mL ng/mL, 2516±982 ng/mL, 3056±1438 ng/mL, and 2367±1029 ng/mL at 0.25, 3, 24, and 120 h, respectively. The accumulation of CHO-PTX in the tumor suggests that cholesteryl drug conjugates are a promising approach for medical treatment of various human cancers.

In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning.

Intravenous lipid emulsion (ILE), a component of parenteral nutrition, consists of a fat emulsion of soy bean oil, egg phospholipids, and glycerin. Case reports suggest that ILE may reverse hypotension caused by acute poisoning with lipophilic drugs such as verapamil, but the mechanism remains unclear. The methods used are the following: (1) measurement of ILE concentration in serum samples from a patient with verapamil poisoning treated with ILE, (2) measurement of free verapamil concentrations in human serum mixed in vitro with increasing concentrations of ILE, and (3) measurement of murine ventricular cardiomyocyte L-type Ca(2+) currents, intracellular Ca(2+), and contractility in response to verapamil and/or ILE. Maximum patient serum ILE concentration after infusion of 1 L ILE over 1 h was approximately 1.6 vol%. In vitro GC/MS verapamil assays showed that addition of ILE (0.03-5.0 vol%) dose-dependently decreased the free verapamil concentration in human serum. In voltage-clamped myocytes, adding ILE to Tyrode's solution containing 5 µM verapamil recovered L-type Ca(2+) currents (ICa). Recovery was concentration dependent, with significant ICa recovery at ILE concentrations as low as 0.03 vol%. ILE had no effect on ICa in the absence of verapamil. In field-stimulated intact ventricular myocytes exposed to verapamil, adding ILE (0.5 %) resulted in a rapid and nearly complete recovery of myocyte contractility and intracellular Ca(2+). Our in vitro studies indicate that ILE acts as a lipid sink that rapidly reverses impaired cardiomyocyte contractility in the continued presence of verapamil.

Distribution of Tocopherols and Tocotrienols in Guinea Pig Tissues Following Parenteral Lipid Emulsion Infusion.

BACKGROUND: Tocopherols and tocotrienols possess vitamin E activity and function as the major lipid-soluble antioxidants in the human body. Commercial lipid emulsions are composed of different oils and supply different amounts of vitamin E. The objective of this study was to measure all 8 vitamin E homologs within 4 different commercial lipid emulsions and evaluate their distribution in guinea pig tissues. MATERIALS AND METHODS: The distribution of vitamin E homologs within plasma and guinea pig tissues was determined using a high-performance liquid chromatography (HPLC) system. Lipid hydroperoxides in lipid emulsions were determined using a commercial kit (Cayman Chemical Company, Ann Arbor, MI), and malondialdehyde tissue levels were determined using an HPLC system. RESULTS: The lipid emulsions contained variable amounts of tocopherols, which were significantly different between emulsions. Tocotrienols were present at very low concentrations (≤0.3%). We found no correlation between the amount of vitamin E present in the lipid emulsions and lipid peroxidation. Hydroperoxides were the lowest with an olive oil-based emulsion and highest with a fish oil emulsion. The predominant vitamin E homolog in guinea pig tissues was α-tocopherol. No tissues had detectable levels of tocotrienols. Vitamin E levels (primarily α-tocopherol and γ-tocopherol) were highly variable among organ tissues. Plasma levels were a poor reflection of most tissue levels. CONCLUSION: Vitamin E levels within different lipid emulsions and plasma/tissues are highly variable, and no one tissue or plasma sample serves as a good proxy for levels in other tissues. All study emulsions were well tolerated and did not significantly increase systemic lipid peroxidation.

New Strategy to Reduce Hypertriglyceridemia During Parenteral Nutrition While Maintaining Energy Intake.

BACKGROUND: Hypertriglyceridemia is a frequent metabolic complication associated with fat administration in parenteral nutrition (PN). No clear guidelines have been published on how to proceed once hypertriglyceridemia has been detected. A new strategy could be to substitute the initial fat emulsion with another emulsion with faster clearance. Our objective was to determine the effectiveness in reducing triglyceridemia values, maintaining the caloric intake, and improving nutrition parameters in patients who had moderate hypertriglyceridemia during PN when an olive oil-based fat emulsion (OOFE) was substituted with a multiple-source oil fat emulsion (MOFE). We also assessed the safety of this substitution in hepatic and glycemic profiles. MATERIALS AND METHODS: We performed a retrospective, observational study that included 38 adult patients to whom OOFE in PN was substituted with MOFE when moderate hypertriglyceridemia (≥250-400 mg/dL) was detected. RESULTS: Triglyceridemia values decreased in 36 (94.7%) patients. The mean reduction was 71 (88-22) mg/dL. Fat load was slightly reduced after substitution (-0.14 [-0.23 to 0] g/kg/d; P < .001), but total caloric intake increased from 22.5 (19.7-25.1) to 23.1 (19.8-26.8) kcal/kg/d (P = .053). After substitution, nutrition parameters improved, liver parameters remained unchanged, and insulin requirements increased. CONCLUSION: The substitution of OOFE with MOFE in patients with moderate hypertriglyceridemia during PN resulted in a reduction in triglyceridemia values of about 70 mg/dL. That allowed maintaining the caloric intake and improved nutrition parameters without affecting the hepatic profile. For some patients, insulin requirements increased moderately.

Vitamin K1 distribution following intravenous vitamin K1-fat emulsion administration in rats.

This study investigated vitamin K1 (VK1 ) distribution following intravenous vitamin K1-fat emulsion (VK1 -FE) administration and compared it with that after VK1 injection. Rats were intravenously injected with VK1-FE or VK1 . The organ and tissue VK1 concentrations were determined using high-performance liquid chromatography method at 0.5, 2 and 4 h to determine distribution, equilibrium and elimination phases, respectively. In the VK1-FE group, the plasma, heart and spleen VK1 concentrations decreased over time. However, other organs like liver, lung, kidney, muscle and testis, reached peak VK1 concentrations at 2 h. In the VK1 injection group, the liver VK1 concentrations were significantly higher than those in other organs at the three time points. However, VK1 concentrations in the other organs peaked at 2 h. In addition, in VK1-FE group, the heart, spleen and lung VK1 concentrations were significantly higher than those in the VK1 injection group at the three time points, and the liver VK1 concentration was significantly higher than that in the VK1 injection group at 4 h. The VK1 amount was greatest in the liver compared with the other organs. Thus, the liver is the primary organ for VK1 distribution. The distribution of VK1 is more rapid when injected as VK1-FE than as VK1 .

Evaluation of physical stability of all in one parenteral admixtures for pediatric home care with high electrolytes concentrations / Evaluación de la estabilidad física de preparados parenterales «todo en uno» para atención pediátrica domiciliaria con altas concentraciones de electrolitos

Introduction: The aim of the study was to evaluate stability of 48 total parenteral admixtures for pediatric patients who require home parenteral nutrition. Admixtures contain high amounts of electrolytes. In a clinical practice electrolytes-enrichment of the parenteral nutrition admixtures is a usual demand, especially on the neonatal/pediatric wards. The supplementation of parenteral nutrition with high concentration of electrolytes is a living problem due to decreased stability of lipid emulsions in nutrition admixtures caused by bivalent cations. Methods: Preliminary admixtures were prepared in two-chamber ethylene vinyl acetate bags: amino acids, glucose and electrolytes were combined in one chamber and 20% (w/w) lipid emulsions (SMOFlipid®, Intralipid ® or ClinOleic®) were placed separately in the second chamber. Organic salts of calcium and phosphates were used. Pre-admixtures were stored at +4ºC for up to 21 days after preparation. Each composition of admixtures was prepared twice, because contents of the two chambers were combined at t=0 or after 21 days of storage at +4ºC. Visual observations, globule size distribution (using optical microscopy, laser diffraction and photon correlation spectroscopy methods), pH analyses, zeta potential and surface tension were performed after combining all components together with vitamins. Results: Among 48 of investigated admixtures only two were problematic and other may be stored for at least 21 days at 4°C and completed admixtures demonstrated stability for at least 24 h at room temperature. Conclusion: It was possible to obtain stable admixtures despite of the high concentration of electrolytes (AU)

Introducción: El objetivo del estudio fue evaluar la estabilidad de un total de 48 preparados o mezclas parenterales para pacientes pediátricos con necesidad de nutrición parenteral domiciliaria. Los preparados contienen cantidades elevadas de electrolitos. En la práctica clínica, el enriquecimiento con electrolitos de los preparados de nutrición parenteral es una demanda habitual, especialmente en las unidades neonatales/pediátricas. El complemento de la nutrición parenteral con altas concentraciones de electrolitos es un problema corrriente debido a la menor estabilidad de las emulsiones lipídicas en preparados de nutrición provocada por cationes bivalentes. Métodos: Se prepararon mezclas preliminares en bolsas de etilenvinilacetato de dos cámaras: se combinó amino ácidos, glucosa y electrolitos en una cámara y en la segunda cámara se puso por separado emulsiones lipídicas 20% (w/w) (SMOFlipid®, Intralipid® o ClinOleic®). Se utilizaron sales orgánicas de calcio y fosfatos. Se almacenaron pre-mezclas a +4ºC durante 21 días después de la preparación. Cada composición de mezcla fue preparada dos veces, dado que el contentido de las dos cámaras se combinó en t=0 o después de 21 días después del almacenamiento a +4ºC. Se realizaron observaciones visuales, distribución del tamaño globular (empleando métodos de microscopía óptica, difracción por láser y espectroscopía de correlación fotónica), análisis de pH, potencial zeta y tensión superficial después de combinar todos los componentes a la vez con vitaminas. Resultados: De los 48 preparados investigados solo dos resultaron problemáticos y el resto se pudo almacenar durante al menos 21 días a 4°C y las mezclas completadas presentaron estabilidad durante al menos 24 h a temperatura ambiente. Conclusión: Fue posible obtener preparados estables a pesar de la alta concentración de electrolitos (AU)

Finding new solutions in pediatric parenteral admixtures: how to improve quality and to deal with shortages.

INTRODUCTION: Pediatric parenteral nutrition enables normal growth even of preterm infants. Those children require, however, tailored parenteral nutrition and the creation of such can be challenging due to the risk of instability and shortages. OBJECTIVE: Prototypical parenteral admixtures were created using different calcium salts (organic and inorganic) and different lipid emulsions and tested for stability. 36 of parenteral admixtures containing two types of calcium salts: chloride or gluconolactobionate and different lipid emulsions (SMOFlipid® or Lipofundin MCT/LCT®) were under investigation. METHODS: Preliminary admixtures were prepared in two-chamber bags whereas lipid emulsions were placed separately in the second chamber. Pre-admixtures were stored for up to 21 days at +4ºC. Contents of the two chambers were combined at t = 0 or after 21 days of storage. Physical analysis of completed admixtures (visual inspection, microscopic observation, pH measurement and determination of the size distribution of oily droplets) was carried out after 21 days of the storage. Stability of lipid, commercial emulsions stored in ethylene vinyl acetate (EVA) bags for 42 days was also studied. RESULTS: Irrespectively of the time of storage of preadmixtures and type of calcium salt and different lipid emulsions among 36 total parenteral admixtures only one showed signs of destabilization after preparation and one was unstable when stored for longer than 14 days. All other formulations were qualified to be stable during the study. All investigated commercial lipid emulsions were physically stable in EVA bags even when stored at room temperature. CONCLUSION: The study proved that it was possible to store pre-admixture in EVA bags for 21 days at 4°C as well as that CAN (critical aggregation number) and CaxP (the products of multiplication of calcium and phosphate ions concentration) should not be used as reliable indicators of admixture physical stability. No influence of the type of calcium salts on stability of admixtures was observed.

INTRODUCCIÓN: La nutrición parenteral pediátrica permite un crecimiento normal incluso en lactantes pretérmino. Sin embargo, estos niños requieren una nutrición parenteral a medida y la formulación de tal nutrición puede suponer un reto por el riesgo de inestabilidad y el desabastecimiento. OBJETIVO: Se crearon mezclas parenterales prototípicas utilizando diferentes sales de calcio (orgánicas e inorgánicas) y diferentes emulsiones lipídicas probando su estabilidad. Se investigaron 36 mezclas parenterales que contenían dos tipos de sales de calcio (cloruro o gluconolactobionato) y diferentes emulsiones lipídicas (SMOFlipid® o Lipofundin MCT/LCT®). MÉTODOS: Se prepararon unas pre-mezclas en bolsas bicompartimentales mientras que las emulsiones lipídicas se colocaron de forma separada en la segunda cámara. Las pre-mezclas se almacenaron hasta 21 días a +4º C. Se combinaron los contenidos de ambas cámaras en t = 0 o después de 21 días de almacenamiento. El análisis físico de las mezclas completadas (inspección visual, observación microscópica, medición del pH y determinación de la distribución por tamaño de las gotitas lipídicas) se realizó a los 21 días de almacenamiento. También se estudió la estabilidad de las emulsiones lipídicas almacenadas en bolsas comerciales de acetato de etilen vinilo (AEV) durante 42 días. RESULTADOS: Independientemente del tiempo de almacenamiento de las pre-mezclas y el tipo de sal de calcio y de las diferentes emulsiones lipídicas de entre el total de 36 mezclas parenterales, sólo en una se vieron signos de desestabilización tras la preparación y una fue inestable cuando se almacenó más de 14 días. El resto de las formulaciones se consideraron estables durante el estudio. Todas las emulsiones lipídicas comerciales investigadas fueron estables físicamente en las bolsas de AEV, incluso cuando se almacenaron a temperatura ambiente. CONCLUSIÓN: El estudio mostró que es posible almacenar pre-mezclas en bolsas de AEV durante 21 días a 4° C. También se vio que el NAC (número de agregación crítica) y el CaxP (los productos de la multiplicación de las concentraciones de los iones calcio y fósforo) no deberían utilizarse como indicadores fiables de la estabilidad física de las mezclas. No se observó ninguna influencia del tipo de sal de calcio sobre la estabilidad de las mezclas.

Evaluation of physical stability of all in one parenteral admixtures for pediatric home care with high electrolytes concentrations.

INTRODUCTION: The aim of the study was to evaluate stability of 48 total parenteral admixtures for pediatric patients who require home parenteral nutrition. Admixtures contain high amounts of electrolytes. In a clinical practice electrolytes-enrichment of the parenteral nutrition admixtures is a usual demand, especially on the neonatal/pediatric wards. The supplementation of parenteral nutrition with high concentration of electrolytes is a living problem due to decreased stability of lipid emulsions in nutrition admixtures caused by bivalent cations. METHODS: Preliminary admixtures were prepared in two-chamber ethylene vinyl acetate bags: amino acids, glucose and electrolytes were combined in one chamber and 20% (w/w) lipid emulsions (SMOFlipid®, Intralipid ® or ClinOleic®) were placed separately in the second chamber. Organic salts of calcium and phosphates were used. Pre-admixtures were stored at +4ºC for up to 21 days after preparation. Each composition of admixtures was prepared twice, because contents of the two chambers were combined at t=0 or after 21 days of storage at +4ºC. Visual observations, globule size distribution (using optical microscopy, laser diffraction and photon correlation spectroscopy methods), pH analyses, zeta potential and surface tension were performed after combining all components together with vitamins. RESULTS: Among 48 of investigated admixtures only two were problematic and other may be stored for at least 21 days at 4°C and completed admixtures demonstrated stability for at least 24 h at room temperature. CONCLUSION: It was possible to obtain stable admixtures despite of the high concentration of electrolytes.

Introducción: El objetivo del estudio fue evaluar la estabilidad de un total de 48 preparados o mezclas parenterales para pacientes pediátricos con necesidad de nutrición parenteral domiciliaria. Los preparados contienen cantidades elevadas de electrolitos. En la práctica clínica, el enriquecimiento con electrolitos de los preparados de nutrición parenteral es una demanda habitual, especialmente en las unidades neonatales/pediátricas. El complemento de la nutrición parenteral con altas concentraciones de electrolitos es un problema corrriente debido a la menor estabilidad de las emulsiones lipídicas en preparados de nutrición provocada por cationes bivalentes. Métodos: Se prepararon mezclas preliminares en bolsas de etilenvinilacetato de dos cámaras: se combinó amino ácidos, glucosa y electrolitos en una cámara y en la segunda cámara se puso por separado emulsiones lipídicas 20% (w/w) (SMOFlipid®, Intralipid® o ClinOleic®). Se utilizaron sales orgánicas de calcio y fosfatos. Se almacenaron pre-mezclas a +4ºC durante 21 días después de la preparación. Cada composición de mezcla fue preparada dos veces, dado que el contentido de las dos cámaras se combinó en t=0 o después de 21 días después del almacenamiento a +4ºC. Se realizaron observaciones visuales, distribución del tamaño globular (empleando métodos de microscopía óptica, difracción por láser y espectroscopía de correlación fotónica), análisis de pH, potencial zeta y tensión superficial después de combinar todos los componentes a la vez con vitaminas. Resultados: De los 48 preparados investigados solo dos resultaron problemáticos y el resto se pudo almacenar durante al menos 21 días a 4°C y las mezclas completadas presentaron estabilidad durante al menos 24 h a temperatura ambiente. Conclusión: Fue posible obtener preparados estables a pesar de la alta concentración de electrolitos.

Analytical interferences resulting from intravenous lipid emulsion.

CONTEXT: Lipid resuscitation therapy using intravenous lipid emulsion (IVLE) for drug overdoses has gained widespread use. However, there is little information regarding its adverse effects. OBJECTIVES: We performed lipemic interference studies on typical automated platforms to investigate the potential of lipid resuscitation therapy to interfere with the reliability and turnaround time of analytes that would be of interest in acute intoxications. We also tested methods to minimize interferences. MATERIALS AND METHODS: Serum pools were supplemented with increasing concentrations of Intralipid-20%(®) (0-30%). Analyses were performed on Beckman-Coulter DXC800 and DXI and Roche Modular-P. Analytes demonstrating significant interference were re-measured after centrifugation (14 000 × g for 10 minutes). RESULTS: Triglyceride and glycerol-blanked triglyceride concentrations were similar in IVLE-free samples. However, with addition of IVLE, concentrations were markedly different (139 vs. 76 mmol/L). There was no appreciable interference on the troponin-I, sodium, potassium, chloride, calcium, bicarbonate or urea assays. Albumin and magnesium assays demonstrated significant interference. Amylase, lipase, phosphate, creatinine, total protein, ALT, CK and bilirubin became unmeasurable in IVLE-supplemented samples. Whereas glucose measurement by potentiometry was free of interference, colorimetric methodology was error prone. Centrifugation removed > 90% of glycerol-blanked triglyceride (max = 5.8 mmol/L), dramatically reducing lipid interferences. DISCUSSION: IVLE results in appreciable analytical interferences at concentrations demonstrated in lipid resuscitation therapy. Of particular concern is the marked interference on glucose and magnesium, which may result in unsuccessful and potentially harmful interventions. Major implications for patient care include reporting of incorrect results and delays in the reporting of time-sensitive results. Whenever possible, blood samples should be collected prior to initiating lipid therapy. Interferences can be minimized by brief centrifugation at relatively low speeds on equipment readily available in most core labs.

Pre-treatment with an intravenous lipid emulsion containing fish oil (eicosapentaenoic and docosahexaenoic acid) decreases inflammatory markers after open-heart surgery in infants: a randomized, controlled trial.

BACKGROUND & AIMS: This study assessed the effects of administering a lipid emulsion containing eicosapentaenoic and docosahexaenoic acid before and after open-heart surgery on cytokine production and length of hospital stay in infants. METHODS: Thirty-two infants (40 ± 2.3 weeks gestational age; 10.6 days at time of surgery) undergoing open-heart surgery with cardiopulmonary bypass were randomized to receive an intravenous lipid emulsion with (treatment) or without (control) eicosapentaenoic and docosahexaenoic acid in this prospective, randomized, double-blind, controlled trial. RESULTS: Mean plasma TNF-α concentration was significantly (p = 0.003) lower in the treatment (5.9 pg/mL) compared to the control group (14.8 pg/mL). In infants without sepsis, plasma TNF-α did not differ according to treatment, however when sepsis developed, mean plasma TNF-α was 21.1 pg/mL and 1.5 pg/mL (p = 0.0007) in control and treatment groups, respectively. Plasma TNF-α was positively correlated with length of hospital stay in the control group (p = 0.01), and negatively correlated with length of stay in the treatment group (p = 0.004), with a significant time by treatment interaction (p = 0.02). CONCLUSIONS: Providing a lipid emulsion containing eicosapentaenoic and docosahexaenoic acid reduces TNF-α concentrations in infants undergoing open-heart surgery. Lipid emulsions containing eicosapentaenoic and docosahexaenoic acid may ameliorate the inflammatory response among critically ill infants.

Substitution of standard soybean oil with olive oil-based lipid emulsion in parenteral nutrition: comparison of vascular, metabolic, and inflammatory effects.

CONTEXT: Soybean oil-based lipid emulsions are the only Food and Drug Administration-approved lipid formulation for clinical use in parenteral nutrition (PN). Recently concerns with its use have been raised due to the proinflammatory effects that may lead to increased complications because they are rich in ω-6 polyunsaturated fatty acids. METHODS: This was a prospective, randomized, controlled, crossover study comparing the vascular, metabolic, immune, and inflammatory effects of 24-h infusion of PN containing soybean oil-based lipid emulsion (Intralipid), olive oil-based (ClinOleic), lipid free, and normal saline in 12 healthy subjects. RESULTS: Soybean oil-PN increased systolic blood pressure compared with olive oil-PN (P < 0.05). Soybean oil PN reduced brachial artery flow-mediated dilatation from baseline (-23% at 4 h and -25% at 24 h, both P < 0.01); in contrast, olive oil PN, lipid free PN, and saline did not change either systolic blood pressure or flow-mediated dilatation. Compared with saline, soybean oil PN, olive oil PN, and lipid free PN similarly increased glucose and insulin concentrations during infusion (P < 0.05). There were no significant changes in plasma free fatty acids, lipid profile, inflammatory and oxidative stress markers, immune function parameters, or sympathetic activity between soybean oil- and olive oil-based lipid emulsions. CONCLUSION: The 24-h infusion of PN containing soybean oil-based lipid emulsion increased blood pressure and impaired endothelial function compared with PN containing olive oil-based lipid emulsion and lipid-free PN in healthy subjects. These vascular changes may have significant implications in worsening outcome in subjects receiving nutrition support. Randomized controlled trials with relevant clinical outcome measures are needed in patients receiving PN with olive oil-based and soybean oil-based lipid emulsions.